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PergamonNeuroscience and Biobehavioral Reviews, Vol. 19, No. 4, pp. 533-552, 1995Copyright 1995 Elsevier Science LtdPrinted in the USA. All rights reserved0149-7634/95 $9.50 + 0.00

0149-7634(95)00017-8

Long-term Potentiat ion and N-Methyl-D-aspartate Receptors: Foundations of Memory

and Neurologic Disease?R . A . R I S O N 1 A N D P. K . S T A N T O N

1802 Grevel ia Stree t , South Pasadena, CA 91030, USA

RISON, R. A. AND P. K. STANTON. Long-term potentiation and N-methyl-o-aspartate receptors: Foundations of mernoryand neurologic disease?NEUROS CI BIOBE HAV REV 19(4) 533-552, 1995.--Understanding the physiology of learningand memory is one of the great challenges of neuroscience. The discovery in recent years of long-term potentiation (LTP)of synaptic transmission and the elaboration of the mechanisms involved, in particular the NMDA receptor, offers theprospect not only of improving our understanding of normal memory storage and retrieval, but may also yield insightsabout various neurological and psychiatric clinical disorders. In this review, we begin by examining the different forms,properties, and methods of inducing LTP, followed by a description of molecular mechanisms thought to underlie thephen omen on. Molecul ar structure of the recep tor is discussed, along with the ro les of Ca 2 secon d messenge r systems,synaptic morphology changes, and retrograde messengers in LTP. Finally, implications of the N MDA receptor and LTP inlearning, memory, and certain clinical conditions such as epilepsy, Alzheimer's disease, and schizophrenia are discussed.N-Methyl-D-aspartate Hippocampus Long-term Potentiation Learning and memory Alzheimer's DiseaseEpilepsy Schizophrenia

LONG-TERM POTENTIATION AND N-METHYL-D-ASPARTATERECEPTORS: FOUNDATIONS OF MEMORY AND NEUROLOGICDISEASE?E L U C I D A T I O N o f t h e p h ys io lo g ic a l m e c h a n is m su n d e r ly i n g l e a rn i ng a n d m e m o r y r e m a i n s p e r h a p s o n eo f t h e g r e a t e s t c h a l l e n g e s f a c in g t h e n e u r o s c i e n c e st o d a y . A t n o o t h e r t i m e i n t h e h i s t o r y o f n e u r o s c i e n c eh a v e w e s e e n s u c h a c t i v e i n v e s t i g a t i o n i n t o t h e m o l e c -u l a r u n d e rp i n n in g s o f h o w w e l e a rn a n d r e m e m b e r .O n e o f t h e m o s t s i g n i f i c a n t a d v a n c e s i n t h e p a s t 2 0y e a r s , in t e rm s o f f u r t h e r i n g o u r u n d e r s t a n d i n g o fl e a r n i n g a n d m e m o r y , i s t h e d i s c o v e r y a n d e l a b o r a t i o no f a p h e n o m e n o n c a l le d l o n g - t e rm p o t e n t i a ti o n( L T P ) . B l i s s a n d L C m o f i r s t d e s c r i b e d L T P i n t h er a b b i t h i p p o c a m p a l f o r m a t i o n i n v i v o ( 2 5 ) . T h e yf o u n d t h a t a b r i e f h i g h - f r e q u e n c y e l e c t r i c a l s t i m u l u s( f o r e x a m p l e , a f e w s e c o n d s a t 1 00 H z ) o f p e r f o r a n tp a t h a x o n s i n t h e d e n t a t e g y r u s e v o k e d a n i n c r e a s e i n

s y n a p t i c e x c i t a b il i ty t h a t l a s t e d f o r d a y s t o m o n t h s ( 2 4 )( s e e F ig . 1 f o r a s c h e m a t i c o f h i p p o c a m p a l a n a t o m y ) .A l t h o u g h L T P w a s f i r s t o b s e r v e d a t p e r f o r a n tp a t h w a y s y n a p s e s i n t h e h i p p o c a m p u s a n d , i n d e e d ,w a s t h o u g h t t o p o s s i b l y b e u n i q u e t o th e h i p p o c a m -p u s , L T P h a s s i nc e b e e n r e p o r t e d i n m a n y o t h e r b r a i nr e g i o n s o f t h e v e r t e b r a t e n e r v o u s s y s t e m a s w e l l ,i nc l ud i ng t he neocor t ex (11 ,21 ,205 ,206) , t he l i mb i cfo reb ra i n (178) , and t he v i sua l (7 ,8 ,112 ,172) , mo t o r( 1 8 9 ) , s o m a t o s e n s o r y ( 1 8 0 ) , c i n g u l a t e ( 2 2 2 ) , p y r i f o r m(o l f ac t o ry ) (102 ,204) , and en t o rh i na l co r t i ces (3 ) , andi t h a s e v e n b e e n r e p o r t e d i n s y m p a t h e t i c g a n g l i o n( 3 1) . In t h e m a j o r i t y o f s t u d i e s, L T P h a s b e e n r e p o r t e da t e x c i t a t o r y s y n a p s e s ( 2 6, 3 2) .O n e o f t h e a t t r a c t i v e f e a t u r e s o f L T P a s a m o d e l f o rl e a r n in g a n d m e m o r y i s t h e m a n y l e v e l s a t w h i c h i t c a nb e s t u d i e d , r a n g i n g f r o m t h e p u r e l y b e h a v i o r a l , t oce l l u l a r and mol ecu l ar l eve l s . Th i s r ev i ew wi l l f ocus on

To whom requests for reprints should be addressed.533


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0 3 'o 4 o 4 o"t im e (min)F I G . 1 . ( A ) H i p p o c a m p a l a n a t o m y a n d a r e a s o f L TP . B a s i c h i p p o c a m p a l a n a t o m y w i t ht h e d i r e c t i o n o f i m p u l s e f l o w ( d e n o t e d b y a r r o w s ) . T h e h i p p o c a m p a l f o r m a t i o n i s s it u a t e di n t h e m e d i a l t e m p o r a l l o b e a n d c o n s i s t s o f s e v er a l s tr u c t u r es : t h e h i p p o c a m p u s p r o p e r( A m m o n ' s h o r n ) w h i c h i s c o m p o s e d o f a r e as C A l , C A 3 , a n d C A 4 ; t h e d e n t a t e g y ru s :a n d t h e s u b i c u l u m . T h e r e a r e t h r e e m a j o r e x c i t a t o r y p a t h w a y s w h i c h r u n f r o m t h e s u b i c u -l u re t o t h e C A 1 r e g i o n : (1 ) t h e p e r f o r a n t p a t h w a y , w h i c h r u n s f r o m t h e s u b i c u l u m t o t h ed e n t a t e g y r u s; ( 2 ) t h e m o s s y f i b e r p a t h w a y , w h i c h c o n s i s t s o f a x o n s a r i s i n g f r o m g r a n u l ec e l l s w i t h i n t he de n t a t e gyr us p r o j e c t i ng t o pyr a m i da l c e l l s l y i ng i n t he CA 3 r e g i on ; ( 3 )t h e S c h a e f f e r c o l l a t e r a l s , w h i c h a r e c o m p o s e d o f e x c i t a t o r y c o l l a t e r a l s a r i s i n g f r o mp y r a m i d a l c e l ls in t h e C A 3 r e g i o n p r o j e c t i n g t o t h e p y r a m i d a l c e l l s i n C A l . ( B ) G r a p ho f L T P i n t h e C A 1 r e g i o n o f t h e h i p p o c a m p u s . P l o t o f t h e s l o p e o f a n e x c i t a t o r y s y n a p -t i c po t e n t i a l ( r e c or de d e x t r a c e l l u l a r l y ) , w h i c h i s a n i nd e x o f syna p t i c e f f i c a c y , vs t i m e . T het e s t s t i m ul us w a s g i ve n a t 10 s i n t e r va l s . T o e l i c i t L T P , t w o t r a i ns o f h i gh- f r e qu e nc y s t i m ul i( 1 00 H z / 1 s ) s e p a r a t e d b y 2 0 s , w e r e d e l i v e r e d t o t h e S c h a e f f e r c o l l a te r a l a x o n s . ] A d a p t e df r om ( 159) ] .

LTP from a molecular and neurochemical standpoint andwill concentrate on hippocampal LTP in particular, sincethere is a wide body of growing evidence that hippocam-pal LTP may play a role in certain forms of memory(54,157). In addition, the role of the N-methyl-D-aspar-tate (NMDA) subtype of glutamate receptor in LTP willalso be discussed, along with the significance of both LTPand the NMDA receptor to learning and memory,epilepsy, Alzheimer's disease and schizophrenia.

D I F F E RE N T F O RM S , P RO P E RT I E S A N D M E T H O D S O FI N D U CT I O N O F H I P P O CA M P A L L T PSeveral different forms, properties, and methods ofinduction of LTP have been described. As mentionedabove, LTP was first discovered in the rabbit hippocam-pal formation by Bliss and coworkers (24,25) and wasdescribed as a rapid and persistent activity-dependentenhancement of perforant path synaptic efficacy follow-ing a brief (1-2 s) high-frequency (10(0-400 Hz) electrical


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L T P A N D N M D A R E C E P T O R S 535s t imu l a t i on o f an a f f e ren t i npu t wh i ch l as t ed fo r hour s t omo nths (15,24-26). Figure 1 depic ts basic h ippo cam palana t omy and areas where LTP occu r s ( see F i g . 1 ) .

Elec tr ica l M e thods o f Induc ing L TP (Them Burs tS t imula t ion)S i n c e t h e n , m a n y o t h e r s t i m u l u s p a t t e r n s h a v e b e e nf o u n d t o e f f i c i e n t l y i n d u c e L T P , i n c l u d i n g w h a t i sk n o w n a s t h e t a b u r s t s t i m u l a t i o n , s e v e r a l s h o r t h i g h -f r e q u e n c y ( 1 0 0 H z ) b u r s t s o f a f e w p u l s e s d e li v e r e d a tan i n t e rbu r s t i n t e rva l o f 200 ms (122) , and p r i me d-bur s t s t i mu l a t i on ( a s i ng l e p r i mi ng s t i mu l us , fo l l owed200 ms l a t e r by a bu r s t o f 4 shocks a t 100 Hz) (185) .The s i gn i f i cance o f t he e f f i cacy o f t hese s t i mu l usp a t t e r n s m a y b e t h a t h i p p o c a m p a l p l a s t i c i t y i s i n d u c e dphys i o l og i ca l l y by such synchron i zed bu r s t f i r i ngp a t t e r n s ( 1 6 5 ) . I n d e e d , f u r t h e r s u p p o r t h a s r e c e n t l y

b e e n g i v e n t o t h i s i d e a b y t h e f i n d i n g t h a t t h e t a b u r s ts t i m u l a t io n is o p t im a l f o r t h e i n d u c t i o n o f L T P a t b o t ha p i c a l a n d b a s a l d e n d r i t i c s y n a p s e s i n t h e h i p p o c a m -p u s , p e r h a p s b e c a u s e t h i s f r e q u e n c y m o s t c l o s e l ya p p r o x i m a t e s t h e e n d o g e n o u s h i p p o c a m p a l t h e t ar h y t h m ( 3 4 ) . I n a d d i t i o n , W i n s o n a n d c o l l e a g u e s h a v es h o w n t h a t t i m i n g a s t im u l u s b u r s t t o t h e p e a k o f t h e t ar h y t h m i s o p t i m a l f o r L T P i n d u c t i o n ( 1 6 9 ) . O n t h eo t h e r h a n d , t h e t a s t i m u l a t i o n h a s a l s o b e e n s h o w n t or e v e r s e L T P i n t h e h i p p o c a m p u s v i a a d e n o s i n e r e c e p -t o r s (121) , a f i nd i ng wh i ch may a t f i r s t seem con t r a -d i c t o r y b u t i n a c t u a l i t y m a y s u g g e s t t h a t h i p p o c a m p a lt h e t a r h y t h m p r o m o t e s b o t h t h e i n d u c t i o n a n d r e v e r -s a l o f L T P i n s u c h a w a y a s t o r e f i n e o r s h a r p e nr e c e n t l y e n c o d e d m e m o r y w i t h i n t h e h i p p o c a m p u s(121) .

Non-e lec tr ica l Me tho ds o f Induc ing L TPN o n - e l e c t r i c a l m e t h o d s o f i n d u c i n g l o n g - la s t i n gp o t e n t i a t i o n o f s y n a p t i c t r a n s m i s s i o n , w h i c h c a ns e e m v e r y s i m i l a r t o L T P , h a v e a l s o b e e n e m p l o y e d ,a n d t h e r e h a s b e e n a m u l t i tu d e o f v a r i o u s c h e m i c a l sa n d r e c i p e s f o r i n d u c i n g l o n g - l a s t i n g p o t e n t i a t i o n ,i n c l u d i n g t h e K + c h a n n e l b l o c k e r t e t r a e t h y la m m o n i u m ( T E A ) ( 5 ,9 0 ) , h ig h e x t r a c e l l u l a r C a 2( 2 0 9 ), 1 - o l e o y l - 2 - a c e t y l g l y c e r o l ( a d i a c y l g l y c e r o l

d e r i v a t i v e ) i n a l o w m a g n e s i u m s o l u t i o n ( 1 0 3 ), a lp h a -t o c o p h e r o l ( 2 2 0 ) , n o r e p i n e p h r i n e , w h i c h h a s b e e ns h o w n t o i n d u c e L T P i n t h e d e n t a t e g y r u s ( 2 0 0 , 2 0 2 ) ,t h e m e t a b o t r . o p i c g l u t a m a t e r e c e p t o r ( m G l u R )a g o n i s t a m i n o c y c l o p e n t a n e - l S , 3 R - d i c a r b o x y l a t e( 1 S , 3 R - A C P D ) ( 1 3, 29 ,2 2 2 ), t h e G - p r o t e i n a c t i v a t o rN a F / A I C 1 3 ( 1 7 5 ) , p l a t e l e t - a c t i v a t i n g f a c t o r ( 2 1 6 ) ,s o m a t o s t a t i n ( 1 42 , 14 3 ), a b e e v e n o m k n o w n a s " m a s tc e ll d e g r a n u l a t in g p e p t i d e " a n d a s n a k e v e n o m c a l le d" d e n d r o t o x i n - I " v i a a n i n t e r a c t io n w i t h v o l t a g e -d e p e n d e n t K c h a n n e l s ( 1 1 3) , c y c l ic A M P a n a l o g s( 6 6 ), a n i l l -d e f i n e d 6 9 k D a a c i d i c p e p t i d e ( 2 1 9 ) a n d

i n t e r e s t i n g l y e n o u g h , e v e n a n o x i a - i n d u c e d L T P h a sb e e n d e s c r i b e d , a p h e n o m e n o n w h i c h is p r o b a b l y d u et o t h e r e l e a s e o f g l u t a m a t e ( 4 7 ).T h e r e h a v e a l s o b e e n s u b s t a n c e s f o u n d w h i c h , o nt he i r own , do no t i nduce l ong- l as t i ng po t en t i a t i on , bu tc a n g r e a t l y e n h a n c e i t w h e n g i v e n w i t h a w e a k e l e c tr i -c a l s y n a p t i c s t i m u l a t i o n . A m o n g t h e s e a r e h i s t a m i n e(16 ) , g l yc i ne and d i t h i o t h re i t o l ( a su l fhydry l r educ i ngagen t ) (208) , t he f a t t y ac i ds o l e i c ac i d , myr i s t i c ac i d ,and ca p r i c ac i d (170) , e l eva t i on o f ex t r ace l l u l a r p o t as -s i um (9 ) , ac i d i c f i b rob l as t g rowt h f ac t o r (85 ) , ande p i d e r m a l g r o w t h f a c t o r , w h i c h i s t h o u g h t t o a c t b ye n h a n c e m e n t o f a n N M D A r e c e p to r - m e d ia t e di ncrease i n i n t r ace l l u l a r ca l c i um i on concen t r a t i on (1 ) .O t h e r s u b s t a n c e s i n c l u d e Y M - 1 4 6 7 3 , a n e wt h y r o t r o p in - r e l e a s i n g h o r m o n e a n a l o g w h i c h a ls o h a sb e e n s h o w n t o i m p r o v e e x p e r i m e n t a l l y i n d u c e dm e m o r y d y s f u n c t i o n ( 9 2) , p o l y a m i n e s s u c h a s s p e r m i n e( 3 9) , S D Z E N S 1 63 w h i c h is a s e l e c ti v e m u s c a r i ni c M 1r e c e p t o r a g o n i s t ( 2 7 ) , t r a n s - A C P D ( 1 4 7 ) , a r a c h i d o n i ca c i d ( 2 1 8 ) a n d b o t h n i t r i c o x i d e a n d c a r b o n m o n o x i d e(223) ( see l a t e r ) , and GM1 gang l i o s i de (91 ) .N o r e p i n e p h r i n e , i n a d d i t i o n t o i n d u c i n g L T P i n t h ed e n t a t e g y r u s , h a s a l s o b e e n f o u n d t o e n h a n c e L T P i nt h e C A 3 r e g i o n ( 8 6 ) . E v e n s o m e w e l l - k n o w n d r u g sh a v e b e e n f o u n d t o e n h a n c e L T P , i n c l u d i n g t h e a c e t y l -cho l i nes t e r ase i nh i b i t o r physos t i gmi ne (153) and t hea n t i - c o n v u l s a n t c a r b a m a z e p i n e ( 1 1 5 ) .Varieties and Classif ications o f L TP

A s t h e n a m e i m p l i e s , l o n g - t e r m p o t e n t i a t i o n o u t l a s t so t h e r p r e v i o u s l y d e s c r i b e d f o r m s o f s y n a p t i c e n h a n c e -men t such as augmen t a t i on , f ac i l i t a t i on , and pos t -t e t an i c po t en t i a t i on , t h e l a t t e r o f wh i ch is t he mo s tp e r s i s t e n t a n d c a n l a s t a n y w h e r e f r o m 1 t o 1 0 m i nf o l lo w i n g b r i e f h i g h - f r e q u e n c y s t i m u l a t io n ( 3 2) . T h e r eh a v e b e e n v a r i o u s w a y s o f c l a s s i f y i n g d i f f e r e n c e s i nL T P a c r o s s n e u r o n a l a r e a s , i n c l u d i n g d e c a y t i m econs t an t s (177 ,178) , as soc i a t i ve v s non-assoc i a t i ve(12,15,31,32,36,98,99,123) , wh ich refers to the prop er tyo f a ss o c ia t iv i ty s e e n in N M D A - d e p e n d e n t L T P v s t h el a c k o f a s s o c i a t i v i t y s e e n w i t h N M D A - i n d e p e n d e n tL T P ( s e e l a t e r s e c ti o n s ) , a n d t h e d e p e n d e n c e o n d i f f e r-en t neu ro t r ansmi t t e r r ecep t o r sub t ypes (32 ,80 ,81 ,99 ) .W i t h i n c r e a s i n g i m p r o v e m e n t s i n t h e a v a i l a b l ep h a r m a c o l o g i c a l t o o l s , a n u m b e r o f i n v e st i g a ti o n su s in g a n t ag o n is t s o f N M D A a n d n o n - N M D A s u b t y p e so f g l u t a m a t e r e c e p t o r s a n d m o r e s p e c if i c p r o t e i nk i nase i nh i b i t o r s have expanded on bo t h t he c l ass i f i -c a t i o n s o f m e s s e n g e r a n d e n z y m e s y s t e m s u n d e r ly i n gL T P , a n d o f a c t i v i t y - d e p e n d e n t c h a n g e s i n s y n a p t i cef f i cacy i n genera l .V a r i o u s f o r m s o f s y n a p t i c p o t e n t i a t i o n c a n b ed i v i d e d i n t o N M D A r e c e p t o r - d e p e n d e n t a n d N M D Ar e c e p t o r - i n d e p e n d e n t f o r m s ( 2 2 , 2 2 1 ) . A n o t h e r d i s t i n c -t i o n i s b e t w e e n l o n g - t e r m p o t e n t i a t i o n ( L T P ) a n ds h o r t - t e r m p o t e n t i a t i o n ( S T P ) . S T P d e c a y s w i t hi n 1 h ,is n o t d e p e n d e n t o n p r o t e i n s y n th e s i s, d o e s n o t r e q u i r e


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I l t l l " I1T

I?FIG. 2. Properties of LTP in the CAI Re gion of the Hippocam pus. Long-term potentiation in the CA I regi on of the hippocampu s sho~.scooperativity, associativity, and specificity. A single pyramidal cell is shown receiving we ak and stro ng synaptic inputs by stimulating twodifferent Schaffer collateral a xonal input pathways. [Adapted from (159)]. (A) Tetanic stimulation of the w eak input alone does not causeLTP in the pathway (compare the potential before and after tetanus). A minimum number of axons must be activated. (B) Tetanic stimula-tion of the strong and w eak pathways together causes LTP in both pathways. (C) Tetanic stimulation of the strong input alone causes LTPin the strong pathway but not in the weak one.

N M D A r e c e p t o r a c t i v a t io n a n d , i n t h e p re s e n c e o fp r o t e i n k i n a s e i n h i b i t o r s , la s t s n o l o n g e r t h a n 1 5 - 3 0r a i n ( 2 2 ,1 2 4 , 13 1 , 1 35 , 1 8 3) . I n c o n t r a s t , L T P l a s t s f o rm u c h l o n g e r p e r i o d s , a n d d e p e n d s o n p r o t e i n s y n t h e -s i s t o p e r s i s t ( 1 1 4 ,2 0 1 ) , a l t h o u g h t h e e x a c t r e l a t i o n s h i pb e t w e e n S T P a n d L T P h a s b e e n f a r f r o m c l e ar lyd e f i n e d . I n t h i s m o l e c u l a r c l a s s i f i c a t i o n , S T P o u t l a s t sp o s t - t e t a n i c p o t e n t i a t i o n ( P T P ) , w h i c h i s c l a s s if i e d as af o r m of N M D A r e c e p t o r - in d e p e n d e n t p o t e n t i a ti o n o fs y n a p t ic s t r e n g t h c a u s e d b y t e t a n u s - i n d u c e d b u i l d -u po f p r e s y n a p t i c [ C a 2+] w h i c h e n h a n c e s t r a n s m i t t e rr e le a s e . T h e r e i s a ls o a fo r m o f n o n - N M D A - d e p e n d e n tL T P w h i c h o c c u r s a t m o s s y f i b e r sy n a p s e s i n t h eh i p p o e a m p a l C A 3 r e g i o n . T h is m o s s y f ib e r L T P , ina d d i t io n t o b e i n g n o n - N M D A - d e p e n d e n t ( 80 ), isl a r g e l y p r e s y n a p t i c ( i. e ., o c c u r s v i a a n e n h a n c e m e n t o fp r e s y n a p t i c t r a n s m i t t e r r e l e a s e ) a n d d o e s n o t r e q u i r ep o s t s y n a p t i c C a 2+ i n fl u x , a n d i n t e r e s t i n g l y r e q u i r e s N Ef o r f u l l e x p r e s s i o n ( 8 6 , 2 2 1 ) .N M D A r e c e p t o r - d e p e n d e n t L T P c a n b e fu r th e rd i v i d e d i n t o t h r e e c o m p o n e n t s : L T P 1 , w h e r e p o t e n t i a -t i o n c a n l a s t u p t o 1 .5 h a n d i s b l o c k e d b y k i n a s ei n h i b i t o r s b u t c a n b e p a r t i a l l y e x p r e s s e d i n t h ep r e s e n c e o f p r o t e i n s y n t h e s i s in h i b i to r s ; L T P 2 , w h i c hi s b l o c k e d b y t r a n s l a t i o n a l i n h i b i t o r s o f p r o t e i n s y n t h e -s is , b u t w h i c h a p p e a r s t o b e i n d e p e n d e n t o f g e n ee x p r e s s i o n a n d h a s b e e n s h o w n t o l a s t u p t o 5 d a y s( 1 7 8 ) ; a n d L T P 3 , w h i c h c a n l a s t f r o m s e v e r a l d a y s t ou p t o a b o u t a m o n t h a n d m a y r e q u i r e g e n e e x p r e s s i o n( 97 ). A r e c e n t c o n f o r m a t i o n a n d f u r t h e r e l a b o r a t i o n o ft h e v a r io u s c o m p o n e n t s o f L T P h a s c o m e f r o m t hef i n d i n g s t h a t t h e d i f f e r e n t c o m p o n e n t s c a n b e i n d u c e db y d i f f e r e n t s t i m u l u s t r a i n s, a n d t h a t t h e v a r i o u s e f f e c t st h a t p r o t e i n s y n t h e s i s a n d k i n a s e i n h i b i t o r s h a v e a r e af u n c t i o n o f t h e d i f f e r i n g s t i m u l u s t r a i n s u s e d ( 8 9) .

T h e r e is y e t a n o th e r f o r m o f N M D A r e c e p to r -d e p e n d e n t L T P w h i c h is r e f e r r e d t o as n o n - H e b b i a nL T P . T h i s i n t e r e s t i n g s u b s e t o f L T P s e e m s t o v i o l a t eo n e o f t h e e s s e n t ia l f e a t u r e s o f L T P - - i n p u t - s p e c i f i c i t y( s e e b e l o w ) . T h a t i s t o s a y , p o t e n t i a t i o n o c c u r s n o t o n l ya t t h o s e s y n a p s e s w h e r e t h e r e i s c o i n c i d e n t p r e - a n dp o s t s y n a p t i c a c t i v i t y , b u t e x t e n d s t o s y n a p s e s m a d e b yc o n c u r r e n t l y a c t i v e t e r m i n a l s o n t o n e i g h b o r i n g c e l l sv e r y c l o s e t o g e t h e r , w h e t h e r o r n o t t h e s e c e l l s a r ea c t i v e (2 8 ). D e s p i t e t h e f a c t t h a t th e a b o v e m e n t i o n e ds t u d y w a s d o n e u s i n g h i p p o c a m p a l s l i c e c u l t u r e s a n dt h a t t h e s e c o n d i t i o n s r e p r e s e n t a n a r t i f i c i a l e n v i r o n -m e n t a n d h e n c e m a y b e n o n - p h y si o l o gi c a l , n o n-H e b b i a n L T P p r o v i d e s s u g g e s t e d e v id e n c e f o r ad i f f u s a b l e e x t r a c e l l u l a r m e s s e n g e r i n v o l v e d i n L T Pi n d u c t i o n ( s e e b e l o w ) .Prop erties of" L TP

L T P i s c h a r a c t e r i z e d b y t h r e e e s s e n t i a l c h a r a c t e r i s -t i c s : c o o p e r a t i v i t y , a s s o c i a t i v i t y , a n d i n p u t - s p e c i f i c i t y( s e e F ig . 2 ) . T h e t e r m c o o p e r a t i v i t y r e f e r s t o t h e o b s e r -v a t i o n t h a t a s t i m u l u s i n t e n s i t y t h r e s h o l d n e e d s t o b es u r p a s s e d i n o r d e r t o i n d u c e L T P ( 1 4 9 ) . S t i m u l i o fw e a k i n t e n s i t y w h i c h a c t i v a t e r e l a t i v e l y f e w a f f e r e n tf i b e r s f a i l t o i n d u c e L T P . T h i s i m p l i e s t h a t L T P i n d u c -t i o n d e p e n d s o n t h e s t r e n g t h o f t h e p o s t s y n a p t i cr e s p o n s e , w h i c h i n t u r n c a n b e i n c r e a s e d b y a " c o o p e r -a t i v i t y " o f a c t i v e a f f e r e n t f i b e r s c o n v e r g i n g o n a p o s t -s y n a p t i c s i t e. I t f o ll o w s t h a t a w e a k i n p u t w h i c h i sb e l o w t h e i n t e n s i t y t h r e s h o l d c a n b e r a i s e d a b o v e t h a tt h r e s h o l d i f i t i s p a i r e d s p a t i a l ly a n d t e m p o r a l l y w i t ha n o t h e r s t i m u l u s i n a w a y t h a t s u m s t h e i r p o s t s y n a p t i ca c t i v a t i o n ( 12 3 ,1 4 9 ). T h e r e q u i r e m e n t o f t e m p o r a lp a i r i n g o f p r e - a n d p o s t s y n a p t i c e x c i t a t i o n i s r e f e r r e d


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LTP AND NMDA RECEPTORS 537to as associativity. Finally, input-specificity refers tothe fact that other inputs to the same neurons that arenot active during afferent stimulation do not exhibitLTP, that is, LTP is confined to the activated synapses(4,127) which may suggest that t he ul timate changes insynaptic efficacy are local to the synapse.

A M O LECU LA R CO R RELA TE O F LTP : TH E N M D A RECEP TO R"When an axon of cell A is near enough to excite acell B and repeatedly or persistently takes part in firingit, some growth process or metabolic change takesplace in one or both cells such that A's efficiency, asone of the cells firing B, is increased."These are the words of Donald Hebb, in what hascome to be known as Hebb's postulate for learning asstated over 40 years ago (82). As will be seen, the coreof Hebb's idea, a use-dependent synaptic enhancementbased on an interaction between concurrent pre- and

postsynaptic activity, has been shown to be essentiallycorrect. Many of the properties of LTP can be explainedon a molecular basis by the properties of NMDA, andperhaps other excitatory amino acid receptors.The NMDA receptor can account for many of theproperties of LTP. The NMDA receptor-ion channelcomplex is one of three classes of glutamate receptorswhich are involved in excitatory synaptic transmissionin the brain: NMDA, AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazole proprionic acid), andmetabotropic. Older terminology, which we feel ismore accurate, broke down AMPA receptors intoquisqualate and kainate receptors, each of which arecomposed of different receptor protein subunits thatconfer different conductance properties. Also in theolder terminology, quisqualate receptors were furtherbroken down into quisqualate-A and quisqualate-B,the latter currently being called metabotropic. Both theNMDA and AMPA receptors (kainate andquisqualate-A) are directly gated, whereas themetabotropic receptor (quisqualate-B) is second-messenger linked. The kainate receptor binds theglutamate agonist AMPA and regulates a channelpermeable to Na and K +, whereas the quisqualate-Areceptor also binds A MPA and regulates a Na*-K +channel in a similar manner to the kainate-activatedreceptor-channel. The quisqualate-B receptor (actuallypart of a family of many different subtypes ofmetabotropic glutamate receptors which are coupled todifferent second messengers) stimulates the activity ofphospholipase C (PLC), leading to the formation ofthe second messengers inositol 1,4,5-triphosphate (IP3)and diacylglycerol (DAG) from phosphatidylinositol-4,5-bisphosphate (PIP2) (45,198,214).Finally, the NMDA receptor directly gates a gluta-mate-ac tivat ed channel permeable to Ca 2+, K andNa*, and has several regulatory binding sites forglycine, Zn 2, PCP, MK-801, Mg 2+ (all of which seemto have inhibitory actions on the receptor channelexcept for the glycine site). The channel is normally

blocked by Mg 2 and becomes unblo cked only whenthe postsynaptic cell is adequately depolarized by astrong input from many presynaptic neurons, whichunblocks the channel and allows glutamate to stimu-late the influx o f Na and Ca 2 into the cell (146). TheNMDA receptor is thus unique in being gated by botha chemical agonist and a voltage sensor. The Mg2block is removed only when the postsynapticmembrane is depolarized, and this membrane depolar-ization is normally achieved through the activation ofmany non-NMDA glutamate receptors in closeproximity on the same postsynaptic dendriticmembrane.A basic molecular model for LTP induction can beconstructed as diagrammed in Fig. 3. NMDA andnon-NMDA receptor channels such as quisqualateand/or kainate are probably located near each otheron dendritic spines. During normal low-frequencysynaptic transmission, glutamate is released from thepresynaptic terminal and binds to and acts on bothNMDA and non-NMDA quisqualate/kainate recep-tor-channels. Due to t he Mg 2 block of the NMD Areceptor-channel (but not of either quisqualate orkainate receptors) at the resting potential of thepostsynaptic me mbrane , Na and K flow throu gh thequisqualate and kainate channels, but not throughNMDA ionophores. This results in a local depolar-ization of the postsynaptic membrane in closeproximity to the NMDA receptor-channel, which inturn relieves the Mg 2 block and allows an influx ofCa 2+ into the postsynapt ic cell, provided the localdepolarization occurs while glutamate is still boundto the NMDA receptor-channel (75). This relief ofthe Mgg block o f the N MD A chan nel by a localpostsynaptic depolarization caused by quisqualateand/or kainate receptor-channels, coupled withpresynaptically-released glutamate binding toNMDA receptors, accounts for the associative natureof LTP.Finally, the property of input specificity can beexplained by taking the limited spatial distribution ofpostsynaptic Ca 2 signals into account (76), along wi ththe knowledge that NMDA receptors cluster on theheads of dendritic spines (75). It follows that the peaktransient increase in Ca2 concentration will berestricted spatially to the immediate region of thestimulated postsynaptic site, thus explaining the natureof input specificity of homosynaptic LTP (32). That isto say, whereas electrical potential is integrated overthe whole dendrite, Ca 2. diffuses very slowly and isbuffered, so t hat Ca 2. influx and, hence, LTP isrestricted to the synapse.

THE ROLE OF POSTSY NAPTIC Ca 2+ IN LTPAs has been alluded to above, the second messengerCa + plays a critical role in t he induction of LTP.Indeed, in the prevailing model of LT P induction, onemust assume that an increase in Ca 2+ concen tration in


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538 RISON AND STAN TONA N o r m a l y n a p n c t r a n s m i s s i o n

Glu~ ~ Glu N a +

%~,c

B Duringnitlaho,n

E / ~ t E r .....nsmiH/ / . . . . . (LTP,~ \/ / Ca *' Ca menu n klnase \ X

Glu~ Na*n~ aC 48Glu ~Na*

2 1 ( : - - 1 i 1 -a2*sCalmoduhnlnase ~I [

[ ' I A Morpholog '~ J I

FIG. 3. A simple model for the induction of LTP. According to the prevailing model for theinduction of LTP, both NMDA and non-NMDA receptors (quisqualate and kainate [AMPAreceptors], shown as Q/K in the figure) are located in close proximity of each other ondendritic spines. [Adapted from reference (75)]. (A) During normal low-frequency synaptictransmission, glutamate is released f rom the presynaptic terminal and acts on both theNMDA and non-NMDA (Q/K or AMPA) receptors. Sodium and K ~ flow through the non-NMDA receptor-channels but not through the NMDA ones, due to the Mgz- blockade ofthis channel at normal resting membrane potential. (B) When the postsynaptic membrane isstrongly depolarized by the actions of the non-NMDA receptor channels, as occurs during ahigh-frequency tetanus that induces LTP, depolarization relieves the Mg2+ blockade of theNMDA channel. This allows Na*, K+, and Caz+ to flow through the NMDA channel. Theresulting rise of [Ca '+] in the dendritic spine triggers Ca2+-dependent kinases (Ca2+/calmodulin kinase and kinase C) that are necessary for the induction of LTP. These Ca2~-dependentprocesses are thought to trigger changes in synaptic morphology, including increases in bothNMDA and Q/K (AMPA) sensitivity, which, in turn persistently increase synaptic strength.Once induced, the postsynaptic ce ll may also release a membrane-permeable retrogrademessenger that can act on kinases in the presynaptic terminal to produce sustained enhance-ment of transmitter release that may also be a component of LTP. Also depicted is theopening of voltage-dependent Ca 2+ channels, which may contribute to both postsynaptic andpresynaptic Ca z influx.

the postsynaptic cel l is a necessary second messenger(58,128). It has be en show n that the induc tion of LTPis blocke d by the intracel lular inject ion of EG TA , aCa 2 chel ator (128) and that lowe ring the levels ofextracel lular Ca 2+ prevents the induc tion of LTP (58).It has also been shown that direct act ivat ion of NMDArece ptors raises i ntra cell ular free Ca 2+ levels (130) an dthat a t ransi ent incre ase in ext racel lular Ca 2 inducesan LTP-l ike potent ia t ion (209) . Fur thermore, there i sevidenc e that Ca 2+ influx through NM DA chann els isaug men ted by Ca 2+ release from intracel l ular s tores (6)

possibly via inosi tol 1,4,5-triphosphate (IP3) generatedas a resul t of the act ivat ion of metabotropic glutamatereceptors (one wil l recal l from earl ier thatmetabot ropic g lu tamate receptors are s imply thesecond-messenger l inked quisqualate-B receptors ) aswell as the Ca 2+ which perme ates through NMD Achannels.

How does Ca 2+ influx induce LT P? Several diff erentCa2+-act ivated enzymes have been proposed to play arole, incl udin g calpa in (a Ca2+-activated prote ase)(163), calcineurin (a phospha tase) (78), and certain


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L T P A N D N M D A R E C E P T O R S 5 39p h o s p h o l i p a s e s a n d p r o t e i n k i n a s e s . P r o t e i n k i n a s e C( P K C , a C a 2 + / p h o s p h o l i p i d - d e p e n d e n t p r o t e i n k i n a s e )w a s t h e f i r s t k i n a s e t o b e i m p l i c a t e d i n t h e i n d u c t i o nof LTP (2 ,10 ,110), and b o t h a Ca2+-s ti mu l a ted andr e c e p t o r - m e d i a t e d r is e i n s e c o n d m e s s e n g e r s h a s b e e np r o p o s e d t o a c t i v a t e b o t h p o s t s y n a p t i c a n d p r e s y n a p -t i c P K C , l e a d i n g t o a s u b s t r a t e p h o s p h o r y l a t i o n -m e d i a t e d L T P o f s y n a p t i c t r a n s m i s s i o n .I n h i b i to r s o f P K C a p p l i e d i n a c e rt a i n t i m e f r a m eh a v e b e e n r e p o r t e d t o b l o c k b o t h t h e i n d u c t i o n a n dp e r s i s t e n c e o f L T P ( 1 3 1) a n d i t h a s b e e n s h o w n t h a ti n t r ace l l u l a r i n j ec t i on o f t he ca t a l y t i c subun i t o f PK Ci n d u c e s s y n a p t i c p o t e n t i a t i o n ( 8 7 ) a s d o e s t h e e x t r a -c e l lu l a r a p p l i c a t io n o f s e v e r a l a c t i v a t o r s o f P K C , s u c ha s p h o r b o l e s t e r s . H o w e v e r , t h i s p o t e n t i a t i o n c a n b er e v e r s e d w i t h w a s h o u t o f t h e p h o r b o l e s t e r s ( 1 3 2) . Ac u r r e n t h y p o t h e s i s i s t h a t a p o s t s y n a p t i c k i n a s e i sa c t i v a t e d t r a n s i e n tl y ( f o r l e ss t h a n a f e w m i n u t e sf o l l o w i n g t h e t e t a n u s ) a n d a p r e s y n a p t i c k i n a s e i sa c t i v a t e d f o r l o n g e r p e r i o d s ( b u t f o r l e s s t h a n 1 h ) v i aa m e m b r a n e p e r m e a b l e r e t r o g r a d e m e s s e n g e r ( s e el a t e r s e c t i o n ) a n d t h a t t h e s e k i n a s e s m a y b e t h e g a m m aa n d b e t a i s o f o r m s o f P K C , r e s p e c t i v e l y ( 8 8 ) .F a r l e s s i s k n o w n a b o u t o t h e r k i n a s e s a n d p r o t e a s e si n L T P . C a l m o d u l i n a n d t h e C a 2 + / c a lm o d u l in - d e pe n -d e n t p r o t e i n k i n a s e C a M K I I h a v e b e e n i m p l i c a t e dp r i m a r il y f r o m t h e o b s e r v a t i o n t h a t d e l e t i o n o f t h eg e n e e n c o d i n g a l p h a - C a M K I I , a n i s o f o r m w h i c h i sh e a v i l y e n r i c h e d i n p o s t s y n a p t i c d e n s i t i e s , s e v e r e l yi m p a i r s L T P ( 1 9 6 ). A c y c li c a d e n o s i n e m o n o p h o s p h a t e( c A M P ) d e p e n d e n t p r o t e i n k i n a s e ( p r o t e i n k i n a s e A ,o r P K A ) m i g h t a l s o b e i n v o l v e d , f o r i t h a s b e e n s h o w nt h a t t h e le v e l o f c A M P i s e l e v a t e d in a n N M D A r e c e p -t o r - d e p e n d e n t m a n n e r d u r i n g L T P ( 3 8 ) , a n d t h a t t h ee f fe c t s o f c A M P o n P K A c a n s t im u l a t e a l a te p h a s e o fL T P ( 6 6 ) . I n a d d i t i o n , t h e r e i s e v i d e n c e t h a t p r o t e i nt y r o s i n e k i n a s e s a r e a l s o i n v o l v e d i n L T P ( 1 6 1 ) , a n dH e i n e m a n n a n d c o l l e a g u e s ( 2 0 0 ) h a v e d e m o n s t r a t e d af o r s k o l i n - i n d u c e d L T P .

SYNAPTIC MODIFICATIONS THAT CAUSE THE MAINTENANCEOF LTP

Alteration o f Ion C hannel PropertiesG i v e n t h e a b o v e e v i d e n c e t h a t p r o t e i n k i n a s e s a n dp h o s p h a t a s e s a r e s o m e h o w i n v o l v e d i n n o r m a l l o w -

f r e q u e n c y s y n a p t i c tr a n s m i s s i o n a n d L T P , i t i s r e a s o n -a b l e t o h y p o t h e s i z e t h a t t h e s e e n z y m e s m a y c h e m i c a l lym o d i f y t h e i o n c h a n n e l s t h a t m e d i a t e t h e e x c i t a t o r ys y n a p t i c p o t e n t i a l s t h a t a r e e n h a n c e d d u r i n g L T P ,n a m e l y A M P A a n d N M D A r e ce p to r s. T h e s e m od if i-c a t i o n s w o u l d r e s u l t in c h a n g e s i n c o n d u c t a n c e p r o p e r -t i es l ead i ng t o l a rger exc i t a t o ry pos t synap t i c po t en t i a l s .L e n d i n g c r e d e n c e t o t h e a b o v e i d e a , i n c r e a s e s i n i o nc h a n n e l s e n s i t i v i t y t o g l u t a m a t e h a v e b e e n d e m o n -s t r a t ed fo l l owi ng t he i nduct i on o f LTP. Spec i f i ca l l y ,s t ud i e s h a v e s h o w n a g r a d u a l i n c re a s e i n A M P A ( Q / K )sens i t i v i t y fo l l owi ng t he i nduct i on o f LTP t ha t i s

p r e v e n t e d b y a p o t e n t P K C i n h i b i t o r c a l l e d K - 2 5 2 b(182) , and i t has a l so been shown t ha t t he ca t a l y t i cs u b u n i t o f cy c li c A M P - d e p e n d e n t p r o t e in k i n as e( P K A ) ( m e n t i o n e d e a r l i e r ) c a n d i r e c t l y i n c r e a s eA M P A c h a n n el c o n d u c t a n c e ( 2 1 3 ). C o n c e r ni n g t h eN M D A r e c e p t o r i ts e lf , t h e r e is ev i d e n c e t ha t N M D Ac h a n n e l c o n d u c t a n c e c a n b e i n c r e a s e d b y th e a c t i v a t io no f P K C ( 1 0 4 ) a n d t h a t t h e s u b s e q u e n t p h o s p h o r y l a t i o no f N M D A c h a n ne l s p r o d u c e s a l t e ra t io n s i n th e e x t e n to f t h e M g 2 b l o c k o f t h e s e c h a n n e l s ( 3 7) . T h e r e i s e v e ne v i d e n c e t h a t t h e r e i s a n i n c r e a s e i n r e l e a s e o f e n d o g e -n o u s p r o m o t e r s o f N M D A r e c e p t o r f u n c ti o n , s u c h asarach i don i c ac i d (150) an d IP 3 (139) ( see l a t e r ) fo l l ow-i ng N M D A a c ti va t io n . T h u s, L T P m a y i n v o lv e b o t hl o n g -t e r m i n c re a s e s in A M P A c h a n n e l c o n d u c t a n c ew h i c h p o t e n t i a t e l o w - f r e q u e n c y s y n a p t i c p o t e n t i a l s ,a n d a lo n g - la s t in g p o t e n t i a t i o n o f N M D A c o n d u c t a n c ew h i c h p o t e n t i a t e s s u b s e q u e n t h i g h - f r e q u e n c y a c t i v a -t io n o f N M D A t ra n s m is s io n .Synaptic Structural Changes

T h e r e i s g r o w i n g e v i d e n c e t h a t m o r p h o l o g i c a lchanges may i n par t i cu l a r under l i e t he l ong - l as t i ngm o d i f i c a t i o n s w h i c h a c c o m p a n y L T P a n d t h a t t h e s es t ruc t u ra l change s m ay b e t r i ggered by C a 2 i n f lux andt h e s u b s e q u e n t c a s c a d e o f s e c o n d m e s s e n g e r a c t i v a t i o na n d a l t e r a t i o n o f i o n c h a n n e l p r o p e r t i e s . T h e r e h a v eb e e n r e p o r t s o f e n l a r g e d s u r f a c e a r e a o f s p in e h e a d sa n d i n c r e a s e s i n p o s t s y n a p t i c d e n s i t y f o l l o w i n g t h ei n d u c t i o n o f L T P ( 5 2 ). C h a n g a n d G r e e n o u g h ( 3 5 )h a v e s h o w n t h a t i n c r e a s e s i n s h a f t n u m b e r a n d s e s s i l es p i n e s y n a p s e s ( s y n a p s e s o n s t u b b y , h e a d l e s s s p i n e s )o c c u r w i t h in 1 0 - 1 5 m i n a f t e r L T P - i n d u c i n g t e t a n i z a t i o ni n t h e C A 1 r e g i o n . H o w e v e r , t h e s e c h a n g e s w e r e n o tfound t o per s i s t l onger t han 8 h , so i t appear s t ha tt h e s e p a r t i c u l a r m o r p h o l o g i c a l c o r r e l a t e s a r e t r a n s i e n ti n na t u re .S t r u c t u r a l c h a n g e s i n e x i s t i n g s y n a p s e s a r e p r o b a b l yd r i v e n b y c o r r e s p o n d i n g c y t o s k e l e t a l a lt e r a ti o n s , a n d anu m be r o f s t ud i es ha ve l i nked Ca 2+ i n f lux an d ac t i va-t i o n o f P K C t o c h a n g e s i n c y t o s k e l e t a l a r c h i te c t u r e . I th a s b e e n s h o w n t h a t c y t o s k e l e t a l e l e m e n t s a r e a l t e r e dt h r o u g h a P K C - c a l p a i n i n t e r a c t i o n i n w h i c h c a l p a i n , aC a Z + - d e p e n d e n t n e u t r a l p r o t e a s e , d e g r a d e s P K C ( 1 0 9 )a n d , i n d e e d , i t h a s b e e n p r o p o s e d t h a t s t i m u l a t i o n -i nduc ed i ncreases i n pos t syn ap t i c Ca 2 ac t i va t e ca l pa i n1 , ano t her p ro t ease , wh i ch , by c l eav i ng fod r i n f i l amen t s(po l ypep t i des wh i ch c ross l i nk ac t i n f i l amen t s ) , a l t e r sp o s t s y n a p t i c s t r u c t u r e ( 1 2 6 ) . T h i s i s o n e p r o p o s e dm e c h a n i s m f o r t h e a f o r e m e n t i o n e d e n h a n c e d s e n s it iv -i t y o f A M P A r e c e p t o r s ( 5 0 ) . P e r h a p s a n a l t e r a t i o n i nc y t o s k e le t a l s t ru c t u re c o u l d e n h a n c e b o t h N M D A a n dA M P A r e c e p t o r s e n s i t iv i t y v i a c h a n g e s i n t h e c o n f ig u -r a t i o n o f v a r i o u s b i n d in g s i te s o n t h e r e c e p t o r s , s u c h a st h o s e f o r p h o s p h o r y l a t i o n . I n d e e d , i t h a s b e e n s h o w nt h a t A M P A r e c e p t o r s h a v e s e v er a l co n s e n s uss e q u e n c e s f o r p h o s p h o r y l a t i o n ( 6 8 ) , a n d r e c a l l i t h a sb e e n d e m o n s t r a t e d t h a t N M D A c o n d u c t a n c e c a n


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540 RISON AND STANTONincrease following activation of PKC with subsequentphosphorylation of the channel (37).Presynaptic structural changes have also beensuggested to occur with LTP. For example, it has beenshown that there is an increase in transmitter releasein hippocampal slices both before and after the induc-tion of LTP (23,53,197). One morphological correlateof this may be the finding that there is a redistributionof neurotransmitter vesicles towards the active zone ofthe presynaptic terminal (52). In addition, it has alsobeen observed that [Ca 2+] is elevated in synaptosomesprepared from potentiated dentate gyrus cells almostan hour after the induction of LTP (129), and this mayvery well explain the ability of the presynaptic site torelease an increased amount of transmitter followingLTP induction.

IS LTP MAINTA INED BY PRESYNAPTIC OR POSTSYNAPTICALTERATIONS?: QUANTAL ANALYSIS AND RETROGRAD EMESSENGERS

The notion of a retrograde messenger involved in theinduction of LTP arose from a number of observationswhich seem explicable only if the postsynaptic dendrit ecan signal the presynaptic terminal in some way.Among these are the discovery that LTP can spread toneighboring synapses (non-Hebbian LTP) (28), thefindings of quantal analysis studies (see below), andfrom an attempt to reconcile the idea that a postsy-naptic locus for induction of potentiation might bemaintained by a presynaptic change. Specifically, theidea of a retrograde messenger began with observa-tions that postsynaptic injection of Ca 2 chelatorsblocked the induction of LTP (128), indicating thatpostsynaptic Ca 2 was an essential trigger. However, itwas subsequently found that presynaptic glutamaterelease was enhanced during LTP (53), and certainquantal analysis studies further demonstrated presy-naptic alterations involved in LTP (23,53,129,197). Itwas this sequence of events which led to the idea of aretrograde messenger, a substance released frompostsynaptic cells (40,70,190,191) or nearby glia (192)during tetanic stimulation that could diffuse into presy-naptic terminals, and produce unknown alterationsthat may cause the induction and/or maintenance ofLTP. Indeed, from mention of the studies in the previ-ous section concerning presynaptic morphologicalchange, the notion of a retrograde messenger involvedin both pre- and postsynaptic dialog becomes moreappealing.Recently, the use of quantal analysis has furtherfueled the presynaptic/postsynaptic controversy.Briefly summarized, almost 40 years ago del Castilloand Katz proposed the quantal hypothesis, whichstates that synaptic transmission involves the proba-bilistic release of multimolecular packets of neuro-transmitter, probably corresponding to the contents ofsingle synaptic vesicles (51). If certain assumptions aremade about the statistics of the release, analysis of

trial-to-trial fluctuations in postsynaptic responses, toeither spontaneously released or low-intensity stimu-lus-evoked quanta, estimates of both the number ofquanta released and the size of their postsynaptic effectmay be obtained. The smallest observed responserepresents a single quanta, or indivisible packet ofmany transmitter molecules. This, in turn, allows thequantification of the relative contributions of pre- andpostsynaptic changes to LTP, that is, if the averagenumber of packets released on average goes up, thiscorresponds to a presynaptic locus, and if the averageamplitude of the response per packet goes up, thisindicates a postsynaptic site of modification (120).Despite some important difficulties of applyingquantal analysis to many central synapses, it has beenwidely used, while yielding conflicting results. Earlystudies in the CA1 area of the hippocampus suggestedmore of a presynaptic locus for LTP (211), as havemore recent ones that utilized lower noise patch clamprecordings (17,134,136,212), while others have leanedtowards a postsynaptic site (65). The most recentstudies have pointed to the more realistic notion of amixture of both a pre- and postsynaptic locus(116,120). The current synthesis is that both increasedglutamate release and many postsynaptic modificationsare all probably contributing to LTP, perhaps withdiffering rates of onset and duration.As can be seen from the above pharmacological andquantal analysis studies, the notion of a retrogrademessenger was needed. That is, if LTP requires postsy-naptic NMD A activa tion and Ca 2 influx, and if acomponent of LTP is enhancement of presynapticrelease, then there must be some way the postsynapticside signals the presynaptic terminal. One can postu-late certain properties that a retrograde messengermight have, such as production and/or release inresponse to the activation of postsynaptic NMDAreceptors, an increase in synaptic availability followingthe induction of LTP, a relatively fast transit time (i.e..minutes), easy diffusability from the postsynapticdendrite through membranes to the presynaptic site.and inhibitors of the production and release of a retro-grade messenger should result in blocking the induc-tion of LTP. Proteins were the first candidates for thisretrograde messenger to be considered, based onfindings that protein content of hippocampalperfusates was increased following the induction ofNMDA-dependent LTP (55,62,164) and that inhibitorsof protein synthesis blocked LTP (201). Indeed.research continues to consistently show complexpatterns of changes in synthesis of many proteinsfollowing hippocampal LTP (61) including increasedexpression of such substances as tissue-plasminogenactivator (176), and mRNAs for the neurotrophinsBDNF and NT-3 (168). However, given the timerequired for protein synthesis, it is unlikely thatproteins could act as anything other than slow media-tors of a persistent phase of LTP (67). As Bliss andcoworkers (61) have shown, using 35S-methionine to


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L T P A N D N M D A R E C E P T O R S 541l a b e l h i p p o c a m p a l p r o t e i n s a n d h i g h - r e s o l u t i o n t w o -d i m e n s i o n a l g e l e l e c t r o p h o r e s i s , p r o t e i n p r o d u c t i o n i sg r e a t e r 3 h a f te r t h e i n d u c t i o n o f L T P a s c o m p a r e dw i t h 1 h p o s t - t e ta n u s , d i s c o u r a g in g t h e i d e a o f p r o t e i n sa c t in g a s ra p i d m e d i a t o r s o f L T P .A r a c h i d o n i c a c i d a s p r o p o s e d b y B l is s a n d c o l l e a g u e s( 2 1 7 , 2 1 8 ) w a s t h e n e x t c a n d i d a t e t o b e c o n s i d e r e d ,b a s e d o n s t u d i e s s h o w i n g t h a t i n h i b i to r s o f p h o s p h o l i-p a s e A 2 , a n e n z y m e w h i c h c a t a l y z e s t h e r e l e a s e o fa r a c h i d o n i c a c i d f r o m p h o s p h o l i p i d s w i t h i n a c e l l u l a rm e m b r a n e , m a y b l o c k th e i n d u c ti o n o f L T P(141 ,162,217). I t f u lf i ll s t he a fo re m en t i o ned cons t r a i n t sf o r a r e t r o g r a d e m e s s e n g e r , n a m e l y ( a ) r e l e a s e f r o mc u l t u r e d n e u r o n s i n t o a n e x t r a c e l l u l a r m e d i u m b ya c t i v a t io n o f N M D A r e c e p t o r s ( 5 7) , (b ) t h e r e i s a ni n c r e a s e d e f f iu x a n d b i o a v a i la b i l it y o f a r a c h i d o n i c a c i dfo l l owi ng t he i nduct i on o f LT P (42 ) , and ( c ) the app l i -c a t i o n o f a r a c h i d o n i c a c i d t o h i p p o c a m p a l s l i c e s w i t hs i m u l t a n e o u s w e a k s t i m u l a t i o n o f t h e p e r f o r a n t p a t hresu l t s i n a l ong - l as t i ng po t en t i a t i on very much l i keLTP (217 ,218) . I t has a l so been shown (56 ) t ha t a r ach i -d o n i c a c i d c a n b e r e l e a s e d f r o m h i p p o c a m p a l s t r i a t a ln e u r o n s b y a c t i v a ti o n o f q u i s q u a l a t e r e c e p t o r s ( a n ds u b s e q u e n t m e t a b o t r o p i c r e c e p t o r a c t i o n ) , a n o n -N M D A s u b t y p e o f e x c i t a t o r y a m i n o a c i d r e c e p t o r s a so n e w i ll re c a l l. O t h e r f a t t y a c id s h a v e a l s o b e e n s h o w nt o i ncrease synap t i c e f f i cacy , i nc l ud i ng o l e i c ac i d ,myr i s t i c ac i d , and cap r i c ac i d (170) and cou l d a l so p l ayr o l e s a s r e t r o g r a d e m e s s e n g e r s . S o m e o t h e r l i p i d -d e r i v e d c a n d i d a t e s i n c l u d e p l a t e l e t a c t i v a t i n g f a c t o r( 2 1 6 ) w h i c h i s a l s o p h o s p h o l i p a s e A 2 - d e r i v e d a n d1-o l eoy l -2 -ace t y l g l ycero l (103) .N i t r i c o x i d e ( N O ) h a s a l s o a c h i e v e d r e c e n t p o p u l a r -i t y a s a c a n d i d a t e f o r a r e t r o g r a d e m e s s e n g e r , i n p a r tbecause i t i s gaseous , vo l a t i l e , sho r t - l as t i ng and r ap i d .T h e s y n t h e s is o f N O f r o m a r g i n i n e i s c a t a l y z e d b y N Os y n t h e t a s e ( f o r m e r l y c a l l e d N A D P H d i a p h o r a s e ) a n d ,i n d e e d , c o m p e t i t i v e i n h ib i t o rs o f t h is e n z y m e h a v eb e e n s h o w n t o b l o c k t h e i n d u c ti o n o f L T P(77,152,158). Spec i f ical ly , w he n inhibi tors o f N Os y n t h a s e s u c h a s N G - n i t r o - L - a r g i n i n e a n d N G - m e t h y l -L-arg in i ne a r e i n j ec t ed i n t r ace l l u l a r ly , b l o cka de o f LTPh a s b e e n r e p o r t e d , s u g g e s t i n g t h a t N O s y n t h a s e m a yr e s i d e a t a p o s t s y n a p t i c l o c u s a n d t h a t N O m a y b ep r o d u c e d p o s t s y n a p t i c a l l y . H o w e v e r , i t s h o u l d b en o t e d t h a t e v i d e n c e f o r th e e x p r e s s i o n o f N Os y n t h e t a s e i n h i p p o c a m p a l p y r a m i d a l a n d g r a n u l e c e l l si s s t i l l s o m e w h a t l a c k i n g a n d m a n y i n v e s t i g a t o r s h a v en o t f o u n d a c o n s i s t e n t b l o c k o f L T P u s i n g N Osyn t he t ase i nh i b i t o r s (30 ,74 ) . Never t he l ess , t h i s b l ock -a d e o f L T P b y N O s y n t h e t a s e i n h i b it o r s, w h e n i t c a nb e d e m o n s t r a t e d , is o v e r c o m e b y th e a d d i t i o n o f hi g hcon cen t r a t i ons o f L-arg i n ine , l end i ng fu r t he r supp or t t ot h e n o t i o n o f a n i n t e g r a l r o l e f o r N O s y n t h a s e a n d ,h e n c e , t he p r o d u c t i o n o f N O i n th e m a i n t e n a n c e o fL T P ( 1 6 0 ) . F u r t h e r m o r e , o t h e r s t u d i e s h a v e f o u n d t h a tt h e e x t r a c e l l u la r a p p l i c a t io n o f h e m o g l o b i n , w h i c hb i n d s g a s e s s u c h a s n i t r i c o x i d e , a l s o a t t e n u a t e s L T P( 19 4 ), N O h a s b e e n s h o w n t o e n h a n c e t h e s p o n t a n e o u s

p r e s y n a p t i c r e l e a s e o f t r a n s m i t t e r f r o m h i p p o c a m p a ln e u r o n s ( 1 6 0 ) , a n d o n e w i l l r e c a l l t h a t N O p a i r e d w i t hw e a k t e t a n i c s t i m u l a t i o n c a n e n h a n c e L T P w h e napp l i ed t o h i ppocampal s l i ces (223) .I n t e r e s ti n g l y , th e p r o d u c t i o n o f N O h a s a l s o b e e ni m p l i c a t e d i n i n h i b it i o n o f h i p p o c a m p a l L T P . I z u m i e ta l . ( 9 4 ) h a v e d e m o n s t r a t e d t h a t N O i n h i b i t o r s s u c h a sL - N G - m o n o m e t h y l - a r g i n i n e a n d h e m o g l o b i n c a nr e v e r s e a n N M D A - m e d i a t e d i n h ib i ti o n o f L T Pn o r m a l l y p r o d u c e d b y an a c t iv a t io n o f N M D A r e c e p -t o r s , i n d i c a t i n g t h a t N O c a n i n d e e d i n h i b i t L T P . T h i sp h e n o m e n o n is r e m i n i sc e n t o f th e p r e v i o u s l ym e n t i o n e d i n d u c ti o n a n d r e v e r s a l o f L T P b yt h e t a b u r s t s t i m u l a t i o n ( s e e e a r l i e r ) a n d s u g g e s t s t h a tt h e t i m i ng o f N O r e l e a s e r e l a t i v e t o h i g h - f r e q u e n c ya c t i v a t i o n o f h i p p o c a m p a l s y n a p s e s m a y p l a y ap o s i t i v e o r n e g a t i v e m o d u l a t o r y r o l e i n t h e i n d u c t i o no f L T P , d e p e n d i n g o n p r i o r e v e n t s a t t h e t e t a n i z e ds y n a p s e ( 9 4 ).C a r b o n m o n o x i d e ( C O ) i s a n o t h e r m e m b r a n e -p e r m e a b l e g a s t h a t h a s b e e n s u g g e s t e d t o a c t a s ar e t r o g r a d e m e s s e n g e r . C O h a s p r o p e r t i e s a n d a c t i o n ss i m i l a r t o N O a n d h a s b e e n f o u n d i n t h e h i p p o c a m p u s(60 ,140,210). I t is syn t he s i zed du r i ng t he conv er s i on o fh e m e t o b i li v e rd i n b y t h e e n z y m e h e m e o x y g e n a s e , a n dz i nc p r o t o p o r p h y r i n I X , a n i n h ib i t o r o f h e m e o x y g e -n a s e , h a s b e e n s h o w n t o b l o c k t h e i n d u c t i o n o f L T P i na d o s e - d e p e n d e n t m a n n e r ( 2 2 3) . I n a d d i ti o n , a s w i t hN O , C O a p p l i e d a l o n e d o e s n o t i n d u c e L T P i n t h eC A 1 r e g i o n ; h o w e v e r , i t d o e s e n h a n c e L T P w h e np a i r e d w i t h a w e a k t e t a n i c s t i m u l a t i o n ( 2 2 3 ) . T h e s ef i n d i n g s f u r t h e r i m p l i c a t e t h a t m e m b r a n e - p e r m e a b l eg a s e s s u c h a s C O a n d N O , a l o n e o r i n c o m b i n a t i o n ,

m a y p l a y i n t e g r a l r o l e s a s r e t r o g r a d e m e s s e n g e r s i nsynap t i c s i gna l i ng and LTP.R e g a r d i n g t h e p o s s i b l e r e t r o g r a d e m e s s e n g e r sm e n t i o n e d a b o v e , i t m a y t u r n o u t t h a t c h a n g e s i n t h eex t r ace l l u l a r i on mi l i eu a r e a l so c r i t i ca l t o t he i nduc-t i o n o f L T P . I n f a c t , i t h a s b e e n h y p o t h e s i z e d t h a t K r e l e a s e f r o m a p o s t s y n a p t i c c e l l d u r i n g a t e t a n u s m a yp r o v i d e a s i g n a l t o t h e p r e s y n a p t i c t e r m i n a l v i a a ni n t e r a c t i o n w i t h m e t a b o t r o p i c g l u t a m a t e r e c e p t o r s( 1 4 , 4 4 ) , a n d a p o s s i b l e i n c r e a s e d r e l e a s e o f g l u t a m a t eo n t h e p o s t s y n a p t i c s i t e m i g h t a l s o b e a n e s s e n t i a ls i g n a l i n L T P . I n a d d i t i o n , i t h a s r e c e n t l y b e e n s h o w nt h a t p o t a s s i u m c a n i n d u c e L T P i n h i p p o c a m p a l s l i c e s( 6 4 ) s o t h e r o l e o f e x t r a c e l l u la r K + m a y i n d e e d b ei n t e g r a l i n L T P . I t h a s a l s o b e e n s h o w n t h a t c h a n g e si n e x t r a c e l lu l a r H c o n c e n t r a t i o n c a n m o d u l a t eN M D A - a c t i v a t e d c u r r e n t s a s w e l l ( 2 0 7 ) .

THE SIGNIFICANCE OF THE NMDA RECEPTOR ANDHIPPOCAMPAL LTPW h a t i s t h e f u n c t i o n a l s i g n i f i c a n c e o f h i p p o c a m p a lL T P a n d t he m o l e c u la r f ra m e w o r k o f h o w th e N M D Ar e c e p t o r o p e r a t e s ? C a n c o r r e l a t e s t o t h e f u n c t i o n a lo p e r a ti o n o f t h e N M D A r e c e p to r a n d L T P b e d r a w ni n t e r m s o f le a r n in g a n d m e m o r y a n d e x t e n d e d t o


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542 RISON AND STANTONvarious clinical conditions, not only in which learningand memory are impaired, but other aspects of neuralfunction?Learning and Memory

Are NMD A receptor activation and the induction ofLTP necessary substrates for learning? What is theirsignificance in terms of how we form memories, andwhat specific types of learning and memory areinvolved? Indeed, if LTP does serve a mnemonicfunction, then NMDA antagonists and other agentswhich specifically interfere with induction of LTPshould block the acquisitions of new memories.Traditionally, there have been two classes of animalbehavioral paradigms (usually studied in rats) whichhave been employed in attempting to answer thesequestions: aversively- and appetitively-motivatedbehavior. Using these paradigms, in conjunction withthe technique of intracerebroventricular (ICV) cannu-lar infusion, investigators have administered pharma-cological agents directly into the brains of animalsbeing trained in either aversive or appetitive behaviors,and then observed the rate of acquisition and retentionof the learned behavior compared to control animalsinfused with saline. Using NMDA antagonists in suchparadigms has furthere d our understanding of how andwhat types of learning and memory may be subservedby LTP.In aversively-motivated behavioral paradigms,aversive stimuli are used to induce either passiveavoidance or an escape behavior. Typically, an electri-cal shock is used to study passive avoidance behavior,and escape from water mazes is used to study escapebehavior. Passive avoidance of shock has been gener-ally considered a measure of so-called fear memory,and escape from water mazes has been generallyconsidered a measure of spatial memory. One of thefirst studies implicating LTP in the acquisition ofspatial memory de monstrated that chronic ICV cannic-ular infusion of the competitive NMDA receptorantagonist AP5 (also known as 2-amino-5-phospho-nopentanoic acid or APV) impaired learning of a newspatial task (escape from a water maze) without affect-ing the retent ion of previously learned behaviors (156).Further studies have replicated this finding using eitherAP5 (155,157) or the non-competitive NMDA antago-nist MK-801 (148,154), indicating that the hippocam-pus is one likely site of NMDA receptors contributingto spatial learning. Therefore it seems that the acqui-sition of spatial memory, and not the retention orstorage of previously learned behaviors is mediated bythe induction of NMDA-dependent LTP.Does LTP also underlie the acquisition of otherforms of memory? Indeed, it has been shown that bothMK-801 and AP5 also impair the acquisition of fearmemory in rats. Using electrical shock and passiveavoidance behavior, investigators have shown thatadministration of either MK-801 (20) or AP5 (49,105)

via ICV cannular infusions into hippocampal regions afew minutes before the shock trial impairs the rat'sability to learn to avoid the shock compartment.Further studies using other NMDA antagonists such asPCP, a non-competitive antagonist (49,100), CGS19755(cis-4-phosphono-methyl-2-piperidine-carboxylate. acompetitive antagonist), and CPP [3-(+)-2-carboxy-piperazin-4-yl-propyl-l-phosphate] (166) have allreported similar findings. Pharmacological blockade ofNMDA receptors has also uncovered distinctionsbetween "short-term" and "long-term" memories.Fanselow and colleagues (106) have shown that AP5causes a selective impairment of long-term but notshort-term fear memory and a further study usinghippocampal lesions and fear conditioning hassuggested that hippocampal LTP may mediate theconsolidation of short-term fear memories into long-term memory (108).The general learning impairments produced byNMDA antagonists are not limited to just fear andspatial memory seen in aversive conditioning. Severalstudies have shown deficits in appetitive learning usingNMDA antagonists, suggesting a role for NMDA-mediated LTP in this type of learning paradigm aswell. Costa and coworkers (49) found that PCP andAP5, when administered into hippocampal regions viaICV infusion, increased the number of errors in theradial arm maze test, an appetitive procedure in whichrats must learn to obtain food from baited arms withinthe maze before acquisition, and other studies haveshown similar impairments using the NMDA blockersMK-801 and CPP (33).It is evident from the above findings that NMDAreceptor-mediated hippocampal LTP, and perhapseven neocortical LTP, probably play a role in at leastsome types of learning and memory. Although it is notyet entirely clear the extent to which both NMDAreceptors and LTP are involved, it is reasonable toconclude that both the NMDA receptor and LTP aresomehow involved in the acquisition phase of memory,since in all of the experimental situations describedabove, behavioral impairments were only seen in theacquisition of new memories and not in the recall ofold ones. It may very well be that LTP, and in partic-ular hippocampal LTP, are involved only in formingnew memories and perhaps the consolidation of newmemories to older, more permanent memories, andthat entirely different cellular mechanisms underlie theactual long-term memories themselves. Alternatively.NMDA receptors and hippocampal LTP may also beinvolved in the processing of already consolidatedmemories.Alzheimer's Disease

Given the putative role of NMDA receptors andLTP in memory, it is reasonable to propose thatimpairments in NMDA receptor function maysomehow be involved in the dementias seen in such


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LTP AND NMDA RECEPTORS 543neurodegenerative diseases as Alzheimer's, particu-larly since patients in the advanced stages of thisdisease have almost a complete inability to form newmemories, whereas long-term stores apparently remainintact. Clinical investigations have provided someevidence suggesting that the dementia and neurode-generation seen in Alzheimer's disease (AD) may beassociated with a dysfunction of excitatory amino acidtransmission, and in particular abnormal functioning ofhippocampal NMDA receptor channels.Young and colleagues (138) were among the first topropose that an overactivity of glutamatergic transmis-sion produces excitotoxic effects in postsynapticneurons. Despite problems in controlling for overallneuronal loss in AD, evidence for a possible loss ofnormal NMDA receptor channel function in AD anddementia has come from ligand studies demonstratingsignificant reductions in glutamate binding preferen-tially (up to 90%, normalized for neuronal numbers)to both NMDA receptors (up to 87%) and AMPAreceptors (up to 69%) in all areas of the ADhippocampus, with very little changes in binding toother receptor types such as kainate and muscariniccholinergic (72), and numerous other studies haveconfirmed these findings (137,138,171,181).Proposed mechanisms that might cause glutamater-gic overactivity in AD include excessive synthesis andrelease of glutamate, faulty or impaired reuptake ordegradation of glutamate, a decrease in the inhibitionof neurons that release glutamate, or perhaps a type ofglutamate-induced apoptotic cell death (i.e., cellulardeath as a consequence of glutamate-induced geneticinteractions). Abnormalities in any of these mecha-nisms could increase local levels of glutamate and leadto neurodegenera tion, possibly via preventing mainte-nance (perhaps metabolic and/or cytoskeletal) ofneuronal axonal and dendritic structure leading to celldeath and the eventual formation of neurofibrillarytangles (138). While the exact mechanisms of cell deathare still unknown, it has been proposed that abnormalglucose metabolism and reduced ATP production,which occurs in both aging and ischemic injury, maylead to an alteration in resting potentials which relievesthe Mg2 block of the NMDA receptor channel. Thiswould enable glutamate and other excitatory aminoacids to cause pe rsistent, excessive Ca 2. flux, leading tocell death (171).

What other factors are responsible for abnormal ionflux through the NMDA receptor channel that couldcontribute to neuronal death in AD? One intriguingtheory views neuronal degeneration as an array ofrelated disorders which arises from one or more alter-ations in calcium-regula ting systems that result in a lossof cellular calcium homeostasis. Mattson et al. (145)have proposed that growth factors stabilize intracellu-lar fr ee Ca 2+ levels and protec t neurons against exces-sive Ca 2~ load leading to ischemic/excitotoxic injury,perhaps via an interaction with NMDA receptorchannels, and tha t alterations of normal growth factor

function may predispose neurons to cellular injury.They further hypothesized that altered beta-amyloidprecursor protein found in the brains of AD patientsmay cause neurodegeneration by impairing apurported neuroprotective function of normal forms ofbeta-amyloid precursor protein which has beensuggested to regulate Ca 2. homeostasis (145).If one recalls the obligatory role of Ca 2 in the induc-tion of LTP and the numerous Ca2-dependent secondmessenger systems thought to be involved, it seemsplausible that abnormalities in these calcium-mediatedsecond messenger systems, secondary to alteredNMDA function, could lead to either neuronal death,or impairments of LTP that might underlie failure toform new memories as seen in AD. If NMDA recep-tor channel overactivity secondary to glutamateoverstimulation is indeed involved in the dementiaprocess, then can the same NMDA antagonists used toimpair learning and memory discussed in the lastsection be used to preserve or increase learning andmemory in AD and other neurodegenerative disor-ders? Although the final conclusions are not yetformed, there is evidence NMDA antagonists mayindeed be useful in such conditions. Initial investiga-tions using animals have shown that the drug Riluzole,which acts as an indirect EAA (i.e., both NMDA andnon-NMDA) antagonist, by decreasing glutamaterelease from nerve terminals, actually improves perfor-mance on a passive avoidance task in animals whoseavoidance response was disrupted by ischemic injury(133). It has also been shown that the disruption ofacquisition of the escape response in a water mazecaused by local injection of NMDA into the hippocam-pus in rats can be prevented with pretreat ment by MK-801. In this particular study, histological analysisshowed that administration of NMDA produced adose-dependent loss of hippocampal cells which wasreduced by the pre -trea tment with MK-801 (184),indicating that MK-801 may serve a protective role andindeed may improve learning and memory undercertain conditions. Another NMDA receptor antago-nist, LY 274614, has also been shown to have neuro-protective effects against excessive NMDA receptoractivation (193), however to date there is unfortunatelyno evidence that it can improve learning and memoryin disease states.The situation is made more complex, however, byfindings that D-cycloserine and milacemide, bothpartial agonists of the glycine binding site of theNMDA receptor, have both shown promise in treat-ment for AD: D-cycloserine was shown to reversespatial memory impairment of hippocampal-lesionedrats (195), and milacemide in clinical trials with ADpatients, has been shown to improve cognitive behav-ior, word recall, and word recognition (84). At first,these results appear to argue for the use of NMDApartial agonists and hence activation of the channel inthe treat ment of dementia. Indeed, studies have shownthat AD patient s have significantly reduced glycine-


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L T P A N D N M D A R E C E P T O R S 5 45N M D A r e c e p t o r c o n t r ib u t i o n s . F o r in s t a n c e , i t h a sb e e n o b s e r v e d t h a t t h e a d m i n i s t r a ti o n o f M g S O 4 t op r e g n a n t w o m e n r a i s e s t h e i r s e i z u r e t h r e s h o l d , p o s s i -b l y b e c a u s e a n i n c r e a s e d e x t r a c e l l u la r c o n c e n t r a t i o n o fM g 2 l e a ds t o i n c re a s e d b l o c k a g e o f t h e N M D A r e c e p -t o r (71 ) . In t e r es t i ng l y , i t has a l so been observed t ha tl ower i ng ex t r ace l l u l a r [Mg2] has b ee n s how n t o ca useb o th N M D A - d e p e n d e n t a nd N M D A - i n d e p e n d en ti n c r e a s e s i n e x c i t a b i l i t y ( 7 9 ) . W h a t e v e r t h e e f f e c t o fM g 2 i s on t he se i zu re t h resho l d , i t seem s t o be on l yt h e r a p e u t i c i n p r e g n a n c y , a n d n o t i n n o n - p r e g n a n tp a t i e n t s . T h i s s u g g e s t s t h e r e m a y b e a l t e r a t i o n s i n t h eM g 2 b l o c k o f N M D A r e c e p t o rs , p e r h a p s d u e t o t h ed i f f e r e n t h o r m o n a l m i l ie u o f p re g n a n c y .A n o t h e r s u c h c l i n i c a l o b s e r v a t i o n i s t h a t m a n yt ri c y c li c a n ti - d e p r e s s a n t s ( T C A ' s ) l o w e r c o n v u l s i v et h r e s h o l d s a n d m a y m a k e p a t i e n t s m o r e p r o n e t os e i z u r e s . L a n c a s t e r a n d D a v i e s ( 1 1 9 ) h a v e s h o w n t h a tt h e tr ic y c l ic d e s m e t h y l i m i p r a m i n e p o t e n t i a t e s N M D Ar e s p o n s e s i n t h e m o u s e c o r t e x , p e r h a p s v i a d ir e c t i n te r -a c t io n w i th t h e N M D A r e c e p t or . A l t h o u g h t h e e x a c tm e c h a n i s m i s s t i l l u n c l e a r , T C A ' s h a v e b e e n s h o w n t oh a v e c o m p l e x e f f e c ts o n n o r e p i n e p h r i n e r e l e a s e( u s u a l ly i n c re a s i n g n o r e p i n e p h r i n e e x t r a s y n a p t i cl e v e ls ) , a t r a n s m i t t e r w h i c h h a s b e e n s h o w n t o r e g u l a t egene ra l i za t i on o f se i zu re ac t i v i ty it se lf , t herefo re , t h ee f f ec t s o f T C A ' s m a y b e s e c o n d a r y r a t h e r t h a np r i m a r y . I n d e e d , r e c a l l t h a t H e i n e m a n n a n d c o l l e a g u e s( 2 0 0) h a v e s h o w n t h e a p p l i c a t i o n o f n o r e p i n e p h r i n e t oh i p p o c a m p a l s li ce s c a n in d u c e a n N M D A - d e p e n d e n tL T P , s o p e r h a p s t h e s e i z u r e t h r e s h o l d - l o w e r i n g e f f e c t so f T C A ' s a r e m e d i a te d b y N E m o d u l at io n o f N M D Ar e c e p t o r s .

T h e s e r e s u l t s c e r t a i n l y i n d i c a t e t h a t f u r t h e r t h e r a -p e u t ic a v e n u e s ta r g e ti n g t h e N M D A r e c e p t o r a n d t h eL T P i t c a n i n d u c e h o l d m u c h p r o m i s e i n t h e t r e a t m e n to f e p i l e p sy .Schizophrenia

G i v e n a l l t h a t w e h a v e s e e n o f t h e p r o b a b l e i n v o l v e -m e n t o f N M D A r e c e p t o r s a n d L T P o f s y n a p ti c tr a ns -m i s s i o n i n l e a r n i n g , m e m o r y , A l z h e i m e r ' s d i s e a s e , a n dep i l epsy , i t i s hard t o i mag i ne t ha t t hey a re no t a l soi n v o l v e d i n s o m e w a y i n n e u r o p s y c h i a t r i c c o n d i t i o n si n w h i c h r e a l i t y p e r c e p t i o n i s a l t e r e d , s u c h a ss c h i z o p h r e n i a . P e r h a p s t h e m o s t c o m p e l l i n g e v i d e n c et h a t t h e N M D A r e c e p t o r i s i n v o lv e d i n s c h i z o p h re n i ai s t h e p h e n o m e n o n o f P C P - i n d u c e d p s y c h o si s .H i s t o r i c a l ly s p e a k i n g , P C P w a s o r i g in a l ly d e v e l o p e d a san anes t he t i c i n t he l a t e 1950s , bu t was found t op r o d u c e , i n m a n y p a t i e n t s , p s y c h o t i c e p i s o d e s c h a r a c -t e r i z e d b y e x c i ta t i o n a n d p a r a n o i a w h i c h t y p i c a ll yl a s t e d f r o m 1 2 - 7 2 h ( 7 3 ) . S u b s e q u e n t s t u d i e s s h o w e dt h a t s u b a n e s t h e t i c d o s e s o f P C P c o u l d a l s o re k i n d l ep r e s e n t i n g s y m p t o m a t o l o g y i n s c h i z o p h r e n i c v o l u n -t e e r s w h o w e r e p r e v i o u s l y i n r e m i s s i o n ( 1 2 5 , 1 8 6 ) .R e c a l l th a t P C P , w h i c h b i n d s in th e N M D A c h a n n el ,i s a n o n - c o m p e t i t i v e N M D A a n t a g o n i s t. I t w a s th e

e l u c i d a ti o n o f t h is P C P - m e d i a t e d n o n - c o m p e t i t i v ei n h ib i ti o n o f N M D A c h a n n e l f u n c ti o n a s th e p r o b a b l eu n d e r l y i n g c a u s e o f t h e p s y c h o m i m e t i c e f f e c t s o f P C Pt h a t s u g g e s t e d a n N M D A r e c e p t o r i n v o l v e m e n t i ns c h i z o p h r e n i a ( 9 6 ) .S t u d i e s i n s y n a p t i c p l a s t i c i t y a n d n e u r o n a l d e v e l o p -m e n t h a v e f u r th e r s u g g e st e d th a t th e N M D A r e c e p t o ra n d L T P m a y p l a y a r o l e i n t h e d e v e l o p m e n t a l e t i o l -o g y o f s c h iz o p h r e n i a . F o r e x a m p l e , i t i s k n o w n t h a t i np r i m a t e s , s y n a p s e s d e v e l o p a t s im i l a r r a t e s i n d i f f e r e n tl a y e r s o f t h e v i s u a l , s o m a t o s e n s o r y , m o t o r , a n dp r e f r o n t a l a r e a s o f t h e c e r e b r a l c o r t e x , a n d s y n a p t i cd e n s i t y i n c re a s e s f o r s e v e r a l m o n t h s a f t e r b ir t h , b e f o r ebeg i nn i ng t o dec l i ne i n a l l l ayer s and a reas (1979) . I t i st h o u g h t t h a t t h e s e le c t i v e , p a t t e r n e d r e d u c t i o n i ns y n a p t i c d e n s i t y , s e e n a f t e r b i r t h i n h u m a n s a n d o t h e rp r i m a t e s is r e g u l a te d b y N M D A - m e d i a t e d p r o c e s se s ,n a m e l y a c e r t a in l e v e l o f N M D A a c t i v a ti o n a p p e a r s t ob e n e c e s s a r y f o r n e u r o n a l s u r v i v a l ( s e e b e l o w ) . R e c a l lt ha t s t ud i es h ave show n t ha t t he ac t i va t i on o f Ca 2+-d e p e n d e n t s e c o n d m e s s e n g e r s y s t e m s r e s u l t s i n s u b s e -q u e n t s t r u c t u r a l c h a n g e s i n t h e s y n a p t i c c y t o s k e l e t o n(109,126) , and aberrat ions in these Ca2+-regulat ings y s t e m s m a y r e s u l t i n a l o s s o f c e ll u la r h o m e o s t a s i s a n dresu l t an t exc i t o t ox i c i t y (145) , con t r i bu t i ng perhaps t ot h e p a t h o p h y s i o l o g y o f A l z h e i m e r ' s d i s e a s e ( 1 3 8) .T h e r e i s g r o w in g e v id e n c e t ha t N M D A r e c e p t o ra c t i v a t i o n d u r i n g c e r t a i n d e v e l o p m e n t a l s t a g e s i sc ruc i a l fo r synapse su rv i va l and can p ro t ec t aga i ns ts y n a p t i c e l i m i n a t io n d u r i n g d e v e l o p m e n t . F o r e x a m p l e ,C o n s t a n t i n e - P a t o n a n d c o w o r k e r s ( 4 3 ) h a v e d e m o n -s t r a t e d t h a t N M D A a c t i v a t i o n d u r i n g n e u r o n a l d e v e l -o p m e n t a l l o w s t e c t a l n e u r o n s t o r e c o g n i z e a n dm a i n t a i n c o a c t i v e a f f e r e n t s y n a p s e s , t h e r e b y p r o t e c t i n gt h e m f r o m s y n a p t i c e l i m i n a t i o n . A l s o , M a t t s o n a n dK a t e r ( 1 4 4 ) , u s i n g i s o l a t e d h i p p o c a m p a l p y r a m i d a lneu rons , have shown t here i s a se l ec t i ve i nh i b i t i on i nd e n d r i t ic p r u n i n g w i t h a p p l i c a t io n o f s u b t o x i c l e ve l s o fg l u t am at e , i nd i ca t i ng t ha t a cer t a i n l eve l o f exc i t a t o ryn e u r a l t r a n s m i s si o n is p r o t e c t i v e o f d e v e l o p i n gs y n a p s e s .I n li g ht o f t h e a b o v e f in d in g s , N M D A r e c e p t o r s m a ywel l p l ay an i mpor t an t ro l e i n t he d i f f e r en t i a l r egu l a-t i o n o f s y n a p t i c t r a n s m i s s i o n i n b o t h n e o n a t a l a n da d u l t b ra i n s . I n d e e d , i f N M D A r e c e p t o r s a r e i n v o l v e di n p run i ng and f i ne t un i ng o f t he neo nat a l b ra i n t o i tsadu l t c i r cu i t con f i gu ra t i on , t hen aber r a t i ons i n t hesep r u n i n g s y s t e m s ( s u c h a s N M D A u n d e r a c t i v i t y ) a tc r i t i c a l t i m e s i n b r a i n d e v e l o p m e n t m a y b e c r i t i c a l t ot h e o n t o g e n e s i s o f s c h iz o p h r e n ia . T h e r e i s e v i d e n c et ha t suc h a c ri t ica l per i od o f neu ra l f i ne- t un i ng occ u r sd u r i n g p r i m a t e a d o l e s c e n c e . F o r e x a m p l e , c e r t a i ns t u d i e s h a v e s h o w n t h a t a p r o f o u n d r e o r g a n i z a t i o n o fb r a i n f u n c t i o n t a k e s p l a c e d u r i n g d e v e l o p m e n t , i nt e r m s o f t h e e a r l y f o r m a t i o n o f s e n s o r y n e u r a l m a p s , ar e d u c t i o n i n t h e a m o u n t o f s le e p a n d r a t e o f n e u r a lm e t a b o l i s m , a d e c r e a s e d c a p a c i t y t o r e c o v e r f u n c t i o naf t e r b ra i n i n j u ry , and , p sycho l og i ca l l y speak i ng , t hea p p e a r a n c e o f a d u l t p r o b l e m - s o l v i n g a b i l it i es ( 6 3) .


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546 RISON AND STANTONFeinberg (63) hypothesized that the selective reductionin overall cortical synaptic density, along with thepreservation of appropriately activated ones, couldaccount for all of these changes, and that a deficit inthis maturational process may underlie those cases ofschizophrenia that emerge during adolescence. Howmight the NMDA receptor be involved in this process?One intriguing theory set forth by Etienne andBaudry (59) proposes that one of the genes modifiedin schizophrenia is directly or indirectly linked to thenormal functioning of the NMDA receptor. Theysuggested that the normal switching on of the expres-sion of an adult form of the NMDA receptor could bedelayed, or perhaps that the adult form itself issomehow altered, resulting in aberrant functioning ofthe receptor during development. Indeed, it has beenshown that the voltage-dependency of NMDA recep-tors is different between neonatal and adult rats (18),and this could correlate with differing neonatal andadult phenotypes. Etienne and Baudry have likenedthe "switch" from the fetal to the adult form of theNMDA receptor to that which has been observed inthe acetylcholine receptor, in which the fetal and adultreceptors have different molecular structures andfunction (151). Conceivably, a similar switch in theexpression of genes coding for the NMDA receptor inthe CNS could occur during the postnatal period. Inconcordance with this, Rakic et al. (1979) proposedthat the synaptic elimination that occurs in the primatecerebral cortex throughout development may beorchestrated by a single genetic signal, which is consis-tent with the idea that a single receptor system may beinvolved (e.g., NMDA receptors).

Could this genetic signal underlie the normal struc-ture and properties of NMDA receptors? Doesschizophrenia result from some type of NMDA under-activity which leads to excess synaptic pruning andaberrant development in adolescence? What aboutpotential drug therapies keyed around these ideas?Holzm~iller and colleagues (107) have found low CSFglutamate levels in schizophrenic patients, whetherthey were treated with neuroleptics or not, which ledthem to propose the idea of a glutamatergic hypoac-tivity in schizophrenia. This idea is certainly consistentwith the phenomenon of PCP-induced psychosis (i.e.,PCP blocks the NMDA channel and, hence, the effectsof glutamate on the NMDA channel). Indeed, it isthought that NMDA receptors are located on certaindopaminergic cell bodies which project into theprefrontal cortical area (101), and that these receptorsmay be naturally involved in stimulating dopaminergictransmission along this mesoprefrontal corticalpathway. Could diminished neural transmission alongthis pathway be responsible for schizophrenia? Couldthe same glycine partial agonists mentioned in refer-ence to Alzheimer's disease be used to increaseNMDA receptor activation and treat schizophrenia?The first studies to look at the effect of glycine inschizophrenia showed a favorable response of

schizophrenic patients to glycine supplementationwhen combined with neuroleptics. Waziri (215) foundthat a significant numbe r of patient s (4 of 11) were ableto reduce their neuroleptic regimen to 10-25% of theirmaintenance doses when supplemented with high-doseoral glycine. Further studies have also yielded promis-ing results, with glycine adjuvant therapy being benefi-cial in at least a few patients (46,188). However, glycinetherapy may be limited by the difficulty in penetratingthe blood-brain barrier, and this has led to the devel-opment of milacemide (mentioned earlier for the treat-ment of Alzheimer's disease), which is an acetylatedprodrug of glycine that readily crosses the blood-brainbarrier (187), and is deacylated in the brain bymonoamine oxidase, converting it to glycine (41,95).However, initial studies using milacemide have beendiscouraging, with either high- or low-dose regimensyielding disappointing results (187). Nevertheless.glycine partial agonist therapy aimed at influencing theNMDA receptor continues to hold promise for thetreatment of schizophrenia (187).Summary and Conclusions

The purpose of this review was to provide anoverview of some of the recent advances in our under-standing of the molecular basis of learning andmemory, and how a molecular framework involvingboth the NMDA subtype of glutamate receptors andLTP of synaptic transmission may be an essentialmechanism of learning and memory, as well as play arole in a number of neurological conditions. We beganby examining the phenomenon of LTP, hippocampalLTP in particular, because of its relevance to memorystorage. We observed that LTP has certain propertiesand characteristics that not only coincided withvoltage-dependent properties of the NMDA receptor,but fit nicely into a simple model of how memoriesmay be formed at a synaptic level.There are essentia l roles for Ca 2+ and a var iety ofother second messenger systems in both the inductionand maintenance of LTP, along with possible synapticmodifications, including structural alterations at boththe pre- and postsynaptic site, alterations of ionchannel properties, and involvement of a possibleretrograde messenger. It remains to be determined towhat extent these phenomenon will turn out toregulate LTP, and possibly learning and memory, andto what ext ent defects in these mechanisms play impor-tant roles in disease states.To the reader we leave the following questions andthe hope that further studies of LTP and the NMDAreceptor will elucidate some answers. Will LTP and theNMDA receptor turn out to be the true molecularfoundations of human memory? To what extent will itunderlie the synaptic machinery of how memories areformed? What about the neurological disordersmentioned? To what extent do LTP and NMDAsystems mediate Alzheimer's Disease? Epilepsy?


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Schizophrenia? Will the NMDA receptor turn out tobe one common thread linking all three disease states?To what extent do endogenous regulators of theNMDA receptor affect the induction of LTP? Can

further drug design based on expanding knowledge ofNMDA receptor function and regulation be used forimproving therapeutic modalities in the treatment ofthe various neurologic disorders discussed?

R E F E R E N C E S1 . Abe , K . ; S a it o , H . Ep i de rm a l g rowt h fac t o r se l ec t i ve ly enhancesNM DA recep t o r -m e d i a t ed i nc rease o f i n t race l l u la r Ca z concen -t ra t ion in ra t h ippocampal neurons. Brain Res. 587(1):102-108;1992.2 . Akers , R . ; Lov i nge r , D . ; Co l l ey , P .; L i nden , D . ; Rou t t enbe rg ,A . Trans l oca t i on o f p ro t e i n k i nase C ac t i v i t y m ay m ed i a t eh i ppocam pa l l ong - t e rm po t en t i a t i on . S c i ence 231 : 587 -589 ;1986.3 . A l onso , A . ; DeCur t i s , M. ; L l i nas , R . P os t synap t i c Heb b i ana n d n o n - H e b b i a n l o n g - t e r m p o t e n t i a t io n o f s y n a pt i c e f f ic a c yi n t he en t o rh i na l co r t ex

Receptores de Aspartato x Memoria

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