Kreitzer Physiology and Pharmacology of Striatal Neurons

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Physiology and Pharmacologyof Striatal NeuronsAnatol C. KreitzerGladstone Institute of Neurological Disease and Departments of Physiology and Neurology,University of California, San Francisco, California 94158;email: [email protected]

Annu. Rev. Neurosci. 2009. 32:127–47

First published online as a Review in Advance onMarch 20, 2009

The Annual Review of Neuroscience is online atneuro.annualreviews.org

This article’s doi:10.1146/annurev.neuro.051508.135422

Copyright c© 2009 by Annual Reviews.All rights reserved

0147-006X/09/0721-0127$20.00

Key Words

basal ganglia, medium spiny neuron, interneuron, dopamine,acetylcholine

AbstractThe basal ganglia occupy the core of the forebrain and consist of evolu-tionarily conserved motor nuclei that form recurrent circuits critical formotivation and motor planning. The striatum is the main input nucleusof the basal ganglia and a key neural substrate for procedural learningand memory. The vast majority of striatal neurons are spiny GABAergicprojection neurons, which exhibit slow but temporally precise spikingin vivo. Contributing to this precision are several different types of in-terneurons that constitute only a small fraction of total neuron numberbut play a critical role in regulating striatal output. This review exam-ines the cellular physiology and modulation of striatal neurons that giverise to their unique properties and function.

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MSN: medium spinyneuron

SNr: substantia nigrapars reticulata

GP: globus pallidus

DA: dopamine

ACh: acetylcholine

Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . 128STRIATAL ANATOMY . . . . . . . . . . . . . . 130

Compartments . . . . . . . . . . . . . . . . . . . . . 130Regions . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

STRIATALNEUROMODULATORS . . . . . . . . . 131Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . 131Acetylcholine . . . . . . . . . . . . . . . . . . . . . . 132

MEDIUM SPINY NEURONS . . . . . . . 132Membrane Properties . . . . . . . . . . . . . . 132Up and Down States . . . . . . . . . . . . . . . 134Neuromodulation . . . . . . . . . . . . . . . . . . 134

INTERNEURONS . . . . . . . . . . . . . . . . . . 135Fast Spiking Interneurons . . . . . . . . . . 135Low-Threshold Spiking

Interneurons. . . . . . . . . . . . . . . . . . . . 136Cholinergic Interneurons . . . . . . . . . . 137

CONCLUSIONS . . . . . . . . . . . . . . . . . . . . 138

INTRODUCTION

The striatum is a convergence point for glu-tamatergic inputs from cortex and thalamus,as well as dopaminergic afferents from themidbrain (Bolam et al. 2000, Kincaid et al.1998, Smith et al. 1994). It is also the source ofthe direct and indirect pathways, two parallelbasal ganglia circuits that are critical for motorfunction and procedural learning (Albin et al.1989, DeLong 1990, Smith et al. 1998). Theimportance of the striatum for basal gangliafunction is highlighted by neurological disor-ders in which striatal function is compromised(Graybiel 2000). In Parkinson’s disease,dopaminergic afferents to the striatum arelost and striatal output via the direct andindirect pathways is altered, resulting in im-paired movement capabilities. In Huntingtondisease, striatal projection neurons becomedysfunctional and degenerate, leading to adisconnection of the striatum from down-stream basal ganglia nuclei and severe motordeficits (Albin et al. 1989, DeLong 1990).Striatal dysfunction is also implicated in other

neurological disorders including dystonia,obsessive-compulsive disorder, and addiction(Breakefield et al. 2008, Graybiel 2008, Hymanet al. 2006). Thus, understanding striatalphysiology is of paramount importance todeciphering basal ganglia function in healthand disease.

Striatal neurons (Figure 1a–d ) have beencharacterized at the anatomical, histochemical,and physiological levels (Kawaguchi et al. 1995,Wilson 1993). Anatomically, striatal cells fallinto two main classes: (a) spiny projection neu-rons and (b) aspiny interneurons. Spiny pro-jection neurons, also known as medium spinyneurons (MSNs), represent the vast majority ofstriatal neurons. They are GABAergic and canbe classified into striatonigral (direct-pathway)and striatopallidal (indirect-pathway) subtypeson the basis of their axonal projections to thesubstantia nigra pars reticulata (SNr) or theglobus pallidus (GP in rodents, external GPin primates) (Smith et al. 1998). MSNs receiveglutamatergic inputs from cortex and thalamusthat terminate predominantly on spines (Kemp& Powell 1971b). In addition, they are a maintarget of midbrain dopaminergic neuron ax-ons that form synapses on MSN dendrites andspine necks (Smith et al. 1994). Histochem-ically, striatonigral MSNs express high levelsof D1 and muscarinic M4 receptors, as well asdynorphin and substance P (Gerfen 1992, Inceet al. 1997). In contrast, striatopallidal MSNsare characterized by their high expression ofdopamine D2 and adenosine A2A receptors, aswell as their immunoreactivity for enkephalin(Gerfen 1992, Schiffmann et al. 1991). Phys-iologically, striatonigral and striatopallidalMSNs exhibit similar properties, although stri-atopallidal MSNs exhibit increased excitability(Kreitzer & Malenka 2007) and each type ofMSN is differentially modulated by dopamine(DA) and acetylcholine (ACh) (Shen et al. 2007,Surmeier et al. 2007).

Aspiny interneurons are far fewer in num-ber and can be categorized anatomically intomedium-sized GABAergic cells and largecholinergic cells (Kawaguchi et al. 1995).Medium-sized GABAergic interneurons can

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a

MSN FS

LTS TAN 20 μm

b

c

e

d

Striatum

Cortex

Figure 1Cell types and functional organization of the rodentstriatum. Schematic representations of (a) a striatalmedium spiny neuron (MSN), (b) a fast spikinginterneuron (FS), (c) a low-threshold spikinginterneuron (LTS), and (d ) a cholinergic tonicallyactive neuron (TAN). Drawings based on imagesfrom Kawaguchi (1993). (e) A coronal schematic ofthe mouse forebrain depicting the cortex andstriatum. Striatal patches ( pink) are illustrated in theright hemisphere, and the dorsolateral, dorsomedial,and ventral divisions of the striatum areschematically illustrated in the left hemisphere.

be further classified histochemically intothree subtypes: (a) parvalbumin-positive; (b)somatostatin-, neuropeptide Y-, and nitric ox-ide synthase-positive; and (c) calretinin-positive(Bennett & Bolam 1993, Chesselet & Graybiel

FS: fast spiking

LTS: low-thresholdspiking

Bacterial artificialchromosome (BAC)transgenic mice:genetically engineeredmice containing a geneof interest andsurrounding genomicregulatory elementsrequired for that gene’scell-type specificexpression pattern

1986, Cowan et al. 1990, Smith & Parent1986, Vincent et al. 1983). Physiologically,these three classes of GABAergic interneuronsdisplay at least two different types of firing pat-terns (Kawaguchi et al. 1995, Tepper & Bolam2004). Parvalbumin-positive neurons exhibitrapid and sustained firing rates in response tocurrent injection and are alternatively known asfast spiking (FS) interneurons. Somatostatin-positive interneurons have lower firing ratesand plateau potentials and are known aslow-threshold spiking (LTS) interneurons.Although calretinin-positive interneuronshave not been classified physiologically, theymay also exhibit some characteristics ofLTS interneurons (Tepper & Bolam 2004).Finally, cholinergic interneurons can be phys-iologically characterized by their significanthyperpolarization-activated currents and spon-taneous activity under physiological conditions(Wilson et al. 1990). Like MSNs, striatalinterneurons receive glutamatergic afferentsfrom cortex and thalamus. However, their out-put is directed primarily to MSNs and otherinterneurons, forming microcircuits capable ofmodulating striatal output (Tepper et al. 2004).

Although investigators have known thebasic physiological properties of striatal celltypes for some time, detailed characterizationof these neurons has proven difficult for severalreasons. In the case of MSNs, it has beenimpossible to differentiate striatonigral andstriatopallidal MSNs in vitro without post hocanalysis because of their similar anatomical andelectrophysiological properties. In contrast,striatal interneurons are straightforward toidentify electrophysiologically (Kawaguchiet al. 1995) but represent only a small fractionof total neuron number. They also appearsimilar to MSNs under the light microscope,making them difficult to selectively targetfor recording. Fortunately, researchers havedeveloped new technologies that enable thevisualization of distinct striatal cell types forcellular and synaptic electrophysiology (Gonget al. 2003). Bacterial artifical chromosome(BAC) transgenic mice expressing green fluo-rescent protein in striatonigral or striatopallidal

www.annualreviews.org • Striatal Physiology and Pharmacology 129

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SNc: SubstantiaNigra pars compacta

ChAT: cholineacetyltransferase

MSNs are now readily available, as are mouselines labeling FS and LTS interneurons. Thesenew tools have led to a resurgence in striatalresearch. This review focuses on the cellularphysiology of different striatal neuron types,including their membrane properties, firingpatterns, and modulation by DA and ACh, thetwo most prominent striatal neuromodulators.

STRIATAL ANATOMY

Compartments

Under the light microscope, the striatumexhibits a relatively uniform appearance.However, it has long been noted that certainneurochemical markers label patches of stria-tum, whereas other markers label the matrix ofneuropil surrounding these patches (Graybiel& Ragsdale 1978, Herkenham & Pert 1981,Olson et al. 1972). This patch/matrix orga-nization (Figure 1e) is particularly importantduring development and segregates MSNs onthe basis of their afferent and efferent projec-tions (Gerfen 1992). Both striatopallidal andstriatonigral MSNs are contained in the patchand matrix compartments (Gerfen & Young1988), although striatonigral MSNs in thepatch compartment project to the substantianigra pars compacta (SNc) rather than to theSNr (Gerfen 1984).

Patches, also known as striosomes, represent∼10% of striatal volume and are distinguishedby dense μ-opioid receptor binding (Herken-ham & Pert 1981), substance P staining (Bolamet al. 1988), and poor staining for cholinergicmarkers (Graybiel & Ragsdale 1978). PatchMSNs receive input primarily from limbicand frontal regions (Donoghue & Herkenham1986, Kincaid & Wilson 1996, Ragsdale &Graybiel 1988), making their connectivitysimilar to MSNs in ventral striatum (Gerfen1985). Patches appear to receive innervationfrom a distinct set of ventral tier SNc neurons( Jimenez-Castellanos & Graybiel 1987, Prensa& Parent 2001), suggesting a possible inde-pendent regulation of striatal output by DA inthese compartments. Given the apparent lack

of cholinergic markers in the patch, cholinergicneuromodulation is probably less prominentin these regions.

In contrast, the matrix is defined by richacetylcholinesterase and choline acetyltrans-ferase (ChAT) staining (Graybiel et al. 1986,Graybiel & Ragsdale 1978), as well as im-munoreactivity for calbinden (Gerfen et al.1985) and somatostatin (Gerfen 1984). MatrixMSNs receive inputs from cortex and thala-mus (Donoghue & Herkenham 1986, Fujiyamaet al. 2006, Sadikot et al. 1992) and connectto both the SNr and the GP (Gerfen 1992).The dense somatostatin and ChAT immunore-activity in the matrix indicate that the axons ofLTS and cholinergic interneurons may be pref-erentially localized to the matrix (Chesselet &Graybiel 1986, Graybiel et al. 1986), whereasthe axons of FS interneurons routinely crosscompartment boundaries (Cowan et al. 1990).The matrix compartment receives the bulk ofsensorimotor striatal afferents and appears tobe strongly regulated by both DA and ACh.

Regions

In primates, the dorsal striatum is divided bythe internal capsule into the medially locatedcaudate nucleus and the laterally positionedputamen. In rodents, descending motor axonbundles perforate the striatum, yielding noclear division between dorsomedial and dorso-lateral striatum. However, these striatal regions(Figure 1e) are anatomically and functionallydistinct in both rodents and primates ( Joel& Weiner 1994, Parent & Hazrati 1995, Yin& Knowlton 2006); the dorsomedial striatumreceives inputs primarily from association cor-tices (Goldman & Nauta 1977, McGeorge &Faull 1989, Ragsdale & Graybiel 1981) and thedorsolateral striatum receives inputs from sen-sorimotor cortex (Kunzle 1975, Liles & Updyke1985, McGeorge & Faull 1989). The ventralstriatum—or nucleus accumbens—represents athird subdivision of the striatum, with distinctproperties from both the dorsomedial andthe dorsolateral striata (Nicola 2007). Theventral striatum, like the patches of the dorsal

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striatum, receives glutamatergic inputs fromfrontal cortex and limbic regions (Brog et al.1993). However, the dopaminergic innervationof the ventral striatum derives from the ventraltegmental area, a separate midbrain nucleus ad-jacent to the SNc (Fields et al. 2007). The ven-tral striatum can be further subdivided into coreand shell regions: Core regions display similar-ity to the dorsal striatum, and shell regions aremore similar to the amygdala (Zahm 2000).

In addition to their connectivity, striatalregions differ in several other important as-pects, including cell-type prevalence and geneexpression patterns. Parvalbumin-positive(FS) interneurons are enriched in the lateralstriatum and are much less evident in themedial striatum (Kita et al. 1990). In contrast,somatostatin-positive (LTS) interneurons havea complementary distribution, with higherdensities in the medial striatum and the ventralstriatum (Gerfen et al. 1985). Differences inregional density and prevalence are speciesspecific: Primates exhibit a higher density ofinterneurons than do rodents (Graveland et al.1985, Wu and Parent 2000). In addition,primates have more calretinin-positive in-terneurons and also exhibit greater densities ofparvalbumin-positive interneurons in the dor-somedial striatum, in contrast to rodents (Wu& Parent 2000). Striatal region gene expressionpatterns also differ. For example, cannabinoidCB1 receptors are highly expressed in ventraland dorsolateral striatum, but not dorsomedialstriatum (Herkenham et al. 1991), whereascalbindin is highly expressed in dorsome-dial striatum but only weakly expressed indorsolateral striatum (Gerfen et al. 1985).

STRIATAL NEUROMODULATORS

Dopamine

DA plays a fundamental role in normal basalganglia function and movement (Heien &Wightman 2006, Nicola et al. 2000, Schultz2007b). The striatum is densely innervated bydopaminergic fibers originating in the SNc(dorsal striatum) and ventral tegmental area

(ventral striatum), and striatal MSNs, GABAer-gic interneurons, and cholinergic interneuronsall express DA receptors. The axons of DA neu-rons arborize extensively in the striatal neu-ropil (Prensa & Parent 2001), giving rise to adense matrix of en passant terminals capableof releasing DA over large regions of striatum.Dopaminergic boutons represent nearly 10% ofall striatal synapses (Groves et al. 1994), and thenearest-neighbor distance between dopaminer-gic boutons is only ∼1.18 μm (Arbuthnott &Wickens 2007). Although some of these ter-minals are found directly adjacent to corticalsynapses at spine necks (Freund et al. 1984,Smith et al. 1994), it is clear that DA reup-take mechanisms are not robust enough to limitspillover away from release sites, suggestingthat DA acts to some degree via volume trans-mission (Cragg & Rice 2004). Consistent withthis hypothesis, most DA receptors are locatedextrasynaptically (Yung et al. 1995), where theyhave been linked to modulation of dendriticconductances and synaptic integration (Nicolaet al. 2000).

Midbrain DA neurons are spontaneouslyactive at low frequencies (1–8 Hz) in vivo. Thisfiring maintains a tonic DA tone that is criticalfor normal striatal function (Schultz 2007b),most likely by activating high-affinity Gi-coupled dopamine D2-type receptors (D2–D4)(Richfield et al. 1989). In response to be-haviorally relevant stimuli (Schultz 2007a),dopaminergic neurons fire bursts of action po-tentials that briefly elevate striatal extracellularDA. These phasic spikes of DA are capable ofactivating lower-affinity Gs-coupled dopamineD1-type receptors (D1, D5) (Richfield et al.1989). In addition, dopaminergic tone can bemodulated on longer timescales in response tobehavioral states including uncertainty, stress,or reward (Schultz 2007a).

DA receptors are present in every celltype in the striatum, although different celltypes express different DA receptor subtypes.Striatonigral and striatopallidal MSNs containtranscripts for both D1- and D2-class DAreceptors, with 10%–20% overlap of D1and D2 receptor transcripts (Surmeier et al.


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1996). However, immunohistochemical studiesindicate only a 1% overlap between D1 andD2 (Ince et al. 1997), implying significantposttranscriptional control of DA receptorexpression in MSNs. The extent of D3–D5receptor expression in MSNs remains unclear.Immunohistochemical and functional evidenceindicates that striatal GABAergic interneuronsexpress primarily D5 receptors (Centonze et al.2003a. Rivera et al. 2002), whereas cholinergicinterneurons express both D2 and D5 receptors(Yan et al. 1997, Yan & Surmeier 1997).

Acetylcholine

ACh represents a second major striatal neu-romodulator (Calabresi et al. 2000, Zhouet al. 2002), which is released into the ex-tracellular space by tonically active choliner-gic interneurons (Bolam et al. 1984, Wilsonet al. 1990). Although cholinergic interneuronsconstitute less than 1% of all striatal neurons(Rymar et al. 2004), their dense and extensiveaxonal arborization ensures widespread releaseof ACh, which like DA may act locally on MSNsynapses (Izzo & Bolam 1988) and have a morewidespread influence via volume transmission(Contant et al. 1996). However, ACh is rapidlydegraded by an efficient extracellular enzyme,acetylcholinesterase, which may serve to limitACh diffusion.

In vivo, cholinergic interneurons exhibittonic low-frequency activity (<10 Hz) that istransiently inhibited in response to visual orauditory cues associated with movement tasks(Aosaki et al. 1995, Apicella et al. 1991, Kimura1986), suggesting that this pause in cholinergicinterneuron firing may be associated with be-haviorally significant cues. The pause appearsto require coordinated synaptic inputs fromboth the SNc and intralaminar thalamic nuclei(Aosaki et al. 1994a, Matsumoto et al. 2001), al-though the precise mechanisms have yet to bedetermined (Bennett & Wilson 1998).

ACh acts at both nicotinic (nAChR) andmuscarinic (mAChR) receptors in the striatum.Nicotinic receptors are pentameric ligand-gated ion channels, which are expressed widely

in the nervous system, particularly in presy-naptic terminals where they can enhance neu-rotransmitter release (Zhou et al. 2002). Inthe striatum, nicotinic receptors are expressedmainly in presynaptic DA terminals and FSinterneurons (Koos & Tepper 2002, Schwartzet al. 1984, Zhou et al. 2002), although thereis some evidence for expression on glutamater-gic terminals, as well. In contrast, mAChRsare expressed widely on MSNs, cholinergic in-terneurons, and GABAergic interneurons. Allfive muscarinic receptor subtypes (M1–M5) areexpressed in the dorsal striatum. M1, M3, andM5 receptors are Gq-coupled, whereas M2 andM4 receptors are Gi-coupled. M1 receptors areexpressed in all MSNs, whereas M4 receptorsare restricted to direct-pathway MSNs (Inceet al. 1997, Yan et al. 2001). In contrast, M2receptors are found exclusively in cholinergicinterneurons (Bernard et al. 1992, Weiner et al.1990), where—along with M4 receptors—theyfunction as cholinergic autoreceptors regulat-ing ACh release (Alcantara et al. 2001, Yan &Surmeier 1996).

MEDIUM SPINY NEURONS

Membrane Properties

The principal neurons of the striatum arethe MSNs, which represent >95% of allstriatal neurons and form the sole output todownstream basal ganglia nuclei (Kemp &Powell 1971a, Rymar et al. 2004). All MSNsshare a similar morphology, but they canbe classified into at least two types on thebasis of their axonal projection patterns (Smithet al. 1998). Striatonigral MSNs project directlyto basal ganglia output nuclei: internal globuspallidus (primates)/entopeduncular nucleus(rodents) and the SNr. In contrast, striatopal-lidal MSNs send axons to the GP, thus onlyindirectly connecting to basal ganglia outputnuclei through a polysynaptic pathway. Stri-atopallidal MSNs appear to receive a bulkof the sensorimotor corticostriatal afferents(Berretta et al. 1997, Parthasarathy & Graybiel1997). This class of afferents project

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topographically from cortex to the striatum; forexample, projections from neighboring barrelsin mouse somatosensory cortex are targetedto discrete neighboring regions of striatalneuropil (Wright et al. 1999). Additionally,both classes of MSNs receive synapses frominterneurons as well as axon collaterals fromother MSNs (Tepper et al. 2004).

Although MSNs do not represent a ho-mogenous population, they do share a numberof physiological properties, and a vast majorityof studies have considered them as a singlecell type. MSNs are characterized by their hy-perpolarized resting membrane potential andlow input resistance (Kita et al. 1984), as wellas by several types of potassium conductancesthat shape their characteristic firing patterns(Nisenbaum & Wilson 1995) (Figure 2a). Atrest, inwardly rectifying potassium channels(Kirs) contribute to their negative restingpotential, low input resistance, and rapidmembrane time constants (Mermelstein et al.1998, Nisenbaum et al. 1996, Uchimura et al.1989). Membrane depolarization inactivatesKirs and activates both fast- (Kv4.2) and slow-inactivating (Kv1.2) A-type potassium currents,as well as a persistent potassium conductance(Kv7), which together yield a slow depolariza-tion and delay to the initial spike (Nisenbaumet al. 1996; Shen et al. 2004, 2005; Surmeieret al. 1989, 1991; Tkatch et al. 2000). De-polarization and spiking also yield calciuminflux, which can activate both small- andlarge-conductance calcium-activated potas-sium channels (Bargas et al. 1999) and limitMSN firing rates.

An early hint that MSN subtypes mightexhibit different physiological properties camefrom studies of Kirs in striatopallidal andstriatonigral MSNs of the nucleus accumbens(Mermelstein et al. 1998). By using posthoc reverse-transcriptase polymerase chainreaction (RT-PCR) analysis to identify MSNsubtypes, striatopallidal MSNs were foundto exhibit Kir currents that inactivated morereadily at hyperpolarized potentials. Giventhe hyperpolarized resting potential of typ-ical MSNs, a reduction in available Kirs in

20 mV100 ms

a

b

c

d

MSN

FS

LTS

TAN

Figure 2Firing properties of striatal neurons. Whole-cellcurrent-clamp recordings were performed fromdifferent striatal cell types. MSNs (a) exhibit lowinput resistance, inward rectification, and a longdelay to initial spiking. FS interneurons (b) have lowinput resistance and a characteristic rapid firingpattern. LTS interneurons (c) have high inputresistance and a sustained plateau potential thatpersists after the end of current injections. LTSinterneurons also display rebound spiking followinghyperpolarizations (not shown here). Tonicallyactive cholinergic interneurons (TANs) (d ) exhibit aprominent hyperpolarization-activated current andbroad spikes with long spike afterhyperpolarizations.


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Inwardly rectifyingpotassium channels:a voltage-sensitivepotassium channel thatis permeable topotassium athyperpolarizedpotentials, but blockedby intracellularpolyamines atdepolarized potentials

Calcium-permeableAMPA receptors:GluR2-lackingreceptors that exhibitcalcium permeabilityand strong inwardrectification that arisesfrom block byintracellularpolyamines atdepolarized potentials

striatopallidal MSNs could significantly in-crease their excitability. Consistent with thisfinding, a more recent study using BAC trans-genic mice found that striatopallidal MSNsfired at higher rates in response to current injec-tions (Kreitzer & Malenka 2007). In addition todifferences in Kir inactivation properties, stri-atopallidal Kirs also display relatively greaterinhibition by muscarinic M1 receptors than dostriatonigral neurons (see below for further dis-cussion) (Shen et al. 2007). Thus, Kir propertiesin striatopallidal MSNs contribute to theirincreased excitability, although excitabilitydifferences persist even during large current in-jections that significantly depolarize MSNs andshould block Kirs (Kreitzer & Malenka 2007),suggesting that other factors may be important.

Up and Down States

Early in vivo studies of striatal MSNs noted ir-regular rhythmic firing patterns that were ac-companied by membrane potential shifts fromhyperpolarized potentials (−90 to −70 mV) tomore depolarized potentials (−60 to −40 mV)(Wilson & Groves 1981), which were subse-quently termed Down and Up states. Spikingwas observed only during Up states, althoughnot every Up state yielded a spike, and evenquiescent MSNs exhibited subthreshold mem-brane potential fluctuations. Recent work indi-cates that Up and Down states are most promi-nent under anesthesia and during slow-wavesleep. In contrast, the waking state is charac-terized by noisy MSN membrane fluctuations.State transitions, although still present, are lessobvious under these conditions (Mahon et al.2006).

Up and Down states in MSNs arise from theintrinsic membrane properties of MSNs as wellas from the nature and coherence of excitatorysynaptic drive from cortex and thalamus (Wil-son & Kawaguchi 1996). The stability of MSNsat rest (Down state) is due to high levels ofKir that limit membrane depolarization in re-sponse to excitatory synaptic inputs. However,if sufficient numbers of glutamatergic inputsbecome active, MSNs can be depolarized

enough to block Kirs, shifting MSNs into theUp state (Blackwell et al. 2003). The Up statepersists as long as sufficient excitatory drive ispresent to maintain depolarization. The mag-nitude of the Up state shift is determined byvoltage-sensitive potassium conductances thatbecome activated following depolarization andserve to limit the extent of synaptically drivendepolarization (Wilson & Kawaguchi 1996).Up states correlated among striatal MSNs,although individual spikes did not (Stern et al.1998), consistent with the hypothesis thatMSNs receive converging inputs from corticalneurons that fire in a correlated—but nottotally synchronous—manner.

Up state transitions also change the prop-erties of synaptic conductances. In the Downstate, excitatory postsynaptic potentials aremediated almost entirely by AMPA receptors.At depolarized Up state potentials, NMDAreceptors are also activated, yielding slowerexcitatory potentials that summate morereadily. Up state transitions also shift thedominant source of synaptic calcium influxfrom calcium-permeable AMPA receptors toNMDA receptors (Carter & Sabatini 2004).Additionally, MSNs express low-voltage-activated l-type calcium channels (Cav1.3),which are activated in the Up state (Carter &Sabatini 2004) and are required for the induc-tion of striatal long-term depression (Choi &Lovinger 1997, Kreitzer & Malenka 2005).

Neuromodulation

Striatal MSNs exhibit numerous ionic conduc-tances that shape their firing properties, andmany of these conductances are sensitive toneuromodulators such as DA and ACh. Stri-atonigral MSNs express D1 receptors, whichregulate sodium, potassium, and calcium chan-nels. Activation of D1 receptors reduces sodiumcurrents (Schiffmann et al. 1995, Surmeieret al. 1992) and enhances Kirs (Pacheco-Canoet al. 1996), both of which are predicted to re-duce MSN excitability. However, D1 receptorsalso enhance l-type currents that are acti-vated in the Up state (Carter & Sabatini 2004,

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Surmeier et al. 1995), giving rise to an enhance-ment of firing when neurons are depolarized(Hernandez-Lopez et al. 1997). Moreover, D1receptors block a slowly inactivating potassiumconductance, which should also enhance firingin the Up state (Nisenbaum et al. 1998). To-gether, these findings suggest that D1 receptoractivation acts as a filter to limit Up state tran-sitions to periods of significant excitatory drive;however, once in the Up state, D1 receptorsfacilitate the firing of striatonigral MSNs.

In contrast, D2 receptors, which are ex-pressed at high levels in striatopallidal MSNs,mainly inhibit MSN firing. Although they re-duce Kir currents (Uchimura & North 1990),which should facilitate Up state transitions,they also inhibit l-type currents and reducespiking in the Up state (Hernandez-Lopez et al.2000). It is intriguing to note that D2 recep-tors, like D1 receptors, exhibit opposite effectsin the Down and Up states. Thus, D2 receptorsmay reduce the excitatory drive necessary forUp state transitions on a timescale of seconds,while increasing the requirement for synchronyon the milliseconds timescale to drive spik-ing. Striatal D2 receptors have also been linkedto mobilization of endocannabinoids (Giuffridaet al. 1999, Yin & Lovinger 2006), which rep-resent a class of lipophilic membrane-derivedsignaling molecules produced in neurons in re-sponse to elevations of intracellular calciumand PLC activation (Piomelli 2003). Striatopal-lidal MSNs exhibit high levels of D2 recep-tor expression and prominently express a formof endocannabinoid-dependent long-term de-pression of glutamatergic synapses (Kreitzer &Malenka 2007).

Cholinergic modulation of MSNs is medi-ated by muscarinic ACh receptors (Yan et al.2001). Activation of M1 receptors, which areexpressed by striatopallidal and striatonigralMSNs, shifts the activation and inactivation oftransient A-type potassium currents to morehyperpolarized potentials (Akins et al. 1990).Thus, when MSNs are in the Down state,A-type potassium currents are partially acti-vated, which will tend to keep MSNs hyper-polarized. However, if excitatory synaptic drive

can overcome these currents and shift MSNsinto the Up state, then these A-type potassiumcurrents will also inactivate more readily andreduce delays to spiking. However, M1 recep-tor activation inhibits Kirs via phospholipaseC activation and depletion of phosphatidyli-nositol biphosphate (PIP2) (Shen et al. 2007).This modulation is selective for striatopallidalMSNs because of their high level of Kir2.3 ex-pression, which is particularly sensitive to PIP2

depletion (Du et al. 2004). M1 activation alsoblocks a persistent potassium current medi-ated by Kv7 channels (Shen et al. 2005). Fur-thermore, M1 activation inhibits N- and P/Q-type calcium channels that couple to calcium-activated potassium channels in MSNs, leadingto enhanced spiking. Together, these findingsindicate that M1 activation increases MSN ex-citability and also enhances the likelihood ofstate transitions in striatopallidal MSNs.

M1 receptors have also been linked to en-docannabinoid production in MSNs, althoughtheir particular role has been disputed. In thehippocampus and cerebellum, activation of Gq-coupled receptors such as M1/3 or mGluR1/5stimulates endocannabinoid production viaphospholipase Cβ. M1 activation in striatalMSNs also facilitated depolarization-evokedendocannabinoid release (Narushima et al.2007). However, a different study concludedthat M1 receptor activation might actuallyinhibit endocannabinoid release via inhibitionof l-type voltage-sensitive calcium channels inMSNs (Wang et al. 2006). Further studies willbe required to clarify this issue.

INTERNEURONS

Fast Spiking Interneurons

FS interneurons represent only a few percentof all striatal neurons (Kita et al. 1990, Rymaret al. 2004), yet they are critical for regulatingstriatal output. Mice with decreased numbersof striatal FS neurons exhibit procedural learn-ing deficits (Marrone et al. 2006), and injec-tions of GABAA antagonists into the putamenincrease MSN firing (Mallet et al. 2005), inhibit


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spiking in the SNr (Yamada et al. 1995), and in-duce dystonia (Yamada et al. 1995, Yoshida et al.1991). Striatal FS interneurons share propertiessimilar to FS interneurons in the hippocam-pus and cortex, such as short-duration spikes,high-frequency firing, and gap junctions withother FS interneurons (Kawaguchi 1993, Kitaet al. 1990) (Figure 2b). They are relativelyenriched in dorsolateral striatum (Bennett &Bolam 1994, Kita et al. 1990), suggesting thatthey play a key role in sensorimotor integration.

FS interneurons receive excitatory synapsesfrom both cortex (Kita 1993, Lapper et al. 1992,Ramanathan et al. 2002) and thalamus (Sidibe &Smith 1999) and receive inhibitory inputs fromother interneurons (Chang & Kita 1992) anda population of globus pallidus neurons (Bevanet al. 1998). Unlike MSNs, which receive smallnumbers of inputs from large numbers of af-ferents, FS interneurons often receive multi-ple synaptic contacts from individual afferentfibers (Ramanathan et al. 2002). Thus, they donot require the same degree of input synchronythat MSNs need to trigger a spike. FS interneu-rons mainly target MSNs, where they form nu-merous proximal synapses capable of inhibitingthe generation of action potentials in MSNs(Bennett & Bolam 1994, Kita 1993, Koos &Tepper 1999, Mallet et al. 2005). This influencearises from the presence of multiple synapticcontacts on MSNs, as well as from their prox-imal location on MSN somata and dendrites(Kubota & Kawaguchi 2000). Researchers es-timate that a single MSN receives inhibitorysynapses from 4–27 FS interneurons, whereas asingle interneuron connects to 135–541 MSNs(Koos & Tepper 1999). MSN synapses ontointerneurons were not observed. In addition,FS interneurons display dendritic gap junc-tions and exhibit electrotonic coupling (Kitaet al. 1990, Koos & Tepper 1999), which canlead to firing synchrony among local interneu-ron populations. However, even bursts in sin-gle interneurons can significantly delay spikingin MSNs (Koos & Tepper 1999). In vivo, FSinterneurons exhibit higher firing frequenciesthan do MSNs and may entrain oscillations be-tween cortex and striatum (Berke et al. 2004).

Desynchronized cortical activity enhances in-terneuron spiking and leads to a dramatic re-duction in MSN spiking activity (Mallet et al.2005) owing to both a reduced excitatory driveon MSNs and an increased inhibitory tone. FSinterneurons have faster response latencies thando MSNs in vivo and may limit the duration ofMSN spiking.

Given the prominent role of FS interneu-rons in regulating MSN spiking, modulationof their firing properties by neuromodulatorsshould be important for striatal function. DAexcites FS interneurons via D5 receptor ac-tivation (Bracci et al. 2002, Centonze et al.2003b) and also via D2-mediated inhibitionof GABAergic afferents onto FS interneurons(Bracci et al. 2002). ACh also excites FS in-terneurons through a direct depolarization me-diated by nondesensitizing nicotinic receptors.Thus, elevations in ACh are predicted to exciteFS interneurons directly. ACh may also indi-rectly facilitate FS firing by enhancing DA re-lease via presynaptic nicotinic receptors (Zhouet al. 2002). In contrast, elevated DA woulddirectly excite FS interneurons but simultane-ously inhibit cholinergic interneurons (see be-low), which could mitigate DA-mediated FSexcitation to some degree.

Low-Threshold Spiking Interneurons

A second type of GABAergic striatal interneu-ron is the LTS cell. LTS interneurons repre-sent a few percent of striatal neurons (Rymaret al. 2004) and exhibit fewer dendriticbranches, as well as less dense and more ex-tensive axonal arborizations relative to FS in-terneurons (Kawaguchi 1993, Vuillet et al.1989). LTS interneurons express somatostatin,neuropeptide Y, and nitric oxide synthase(Chesselet & Graybiel 1986, Kubota et al. 1993,Smith & Parent 1986, Vincent et al. 1983),which likely plays a role in the induction of stri-atal long-term plasticity (Calabresi et al. 1999).Like FS interneurons, LTS interneurons are in-nervated by glutamatergic afferents from bothcortex and thalamus, and in turn form synapsesonto MSNs (Sidibe & Smith 1999, Vuillet et al.

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1989). However, some LTS interneurons alsoappear to receive significant dopaminergic in-nervation (Hidaka & Totterdell 2001, Kubotaet al. 1988). A second population of LTSinterneurons may correspond to calretinin-positive interneurons, which have not been wellcharacterized (Bennett & Bolam 1993, Tepper& Bolam 2004) but appear to lack signif-icant thalamic innervation (Sidibe & Smith1999). Electrophysiologically, LTS interneu-rons are characterized by their plateau po-tentials and low-threshold spikes; in addition,these interneurons display higher input resis-tances and relatively depolarized resting poten-tials (Kawaguchi 1993) (Figure 2c).

Modulation of striatal interneurons has notbeen well characterized, although their inner-vation by dopaminergic axons is prominent inboth dorsal and ventral striata. LTS interneu-rons, like other striatal interneurons, expressD5 receptors (Rivera et al. 2002). Activationof these receptors depolarizes LTS interneu-rons, leading to significant increases in spik-ing (Centonze et al. 2002), although the precisesignaling mechanisms are not clear. MuscarinicM1 and M2 receptors are also expressed in LTSinterneurons (Ariano & Kenny 1989; Bernardet al. 1992, 1998), but their physiological rolesremain unknown.

Cholinergic Interneurons

Cholinergic interneurons, also known as largeaspiny neurons or tonically active neurons, con-stitute only 1%–2% of striatal cells (Kemp &Powell 1971a), but their influence is signifi-cant. They have large (20–50 μm diameter)cell bodies and widespread axonal fields, whichform synapses primarily on MSNs (Bolam et al.1984, Izzo & Bolam 1988, Phelps et al. 1985),but also on FS interneurons (Chang & Kita1992, Koos & Tepper 2002). Cholinergic in-terneurons receive only sparse excitatory inner-vation, which derives primarily from the thala-mus (Lapper & Bolam 1992) and, to a lesserextent, the cortex (Thomas et al. 2000). Theyalso receive inhibitory synapses from MSNs(Bolam et al. 1986). Cholinergic interneurons

can be electrophysiologically distinguished bytheir depolarized resting potential and high-input resistance (Kawaguchi 1993) (Figure 2d ).Cholinergic interneurons fire spontaneouslyin vivo owing to their expression of sodiumcurrents and hyperpolarization-activated cationcurrents (Bennett et al. 2000). Their firing ratesare limited to 2–10 Hz by a prominent after-hyperpolarization following each spike, owingprimarily to calcium-activated potassium chan-nels (Kawaguchi 1992, 1993; Wilson et al. 1990;Wilson & Goldberg 2006).

A characteristic feature of cholinergic in-terneurons in vivo is their pause in tonic firing inresponse to salient cues, including reward andreward prediction (Aosaki et al. 1994b, Graybielet al. 1994, Morris et al. 2004). Although theprecise origins of this pause are still unclear, itrequires both intact thalamic and dopaminer-gic innervation to occur (Aosaki et al. 1994a,Matsumoto et al. 2001). The instrinsic proper-ties of cholinergic interneurons are also critical.Cholinergic interneurons, like MSNs, expressKirs that become unblocked at hyperpolar-ized potentials, and these serve to amplify andprolong the effects of hyperpolarizing inputs(Wilson 2005).

Cholinergic interneurons express both D2and D5 receptors, as well as M2 and M4mAChRs (Bergson et al. 1995, Hersch et al.1994, Levey et al. 1993). D5 receptor activationdepolarizes cholinergic interneurons througha cAMP-dependent mechanism (Aosaki et al.1998), whereas D2 signaling mediates an inhi-bition of voltage-sensitive sodium channels thatreduces excitability (Maurice et al. 2004). Thus,D1-type and D2-type dopamine receptors ex-ert opposite effects on excitability within in-dividual cholinergic interneurons. MuscarinicM2 and M4 receptors, like D2 receptors, re-duce excitability albeit through a differentmechanism involving activation of a potassiumconductance (Calabresi et al. 1998). M2 recep-tors may also function as presynaptic autore-ceptors (Hersch et al. 1994) regulating AChrelease via direct Gβ/γ-mediated inhibition ofpresynaptic calcium channels (Yan & Surmeier1996).


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IndirectMSN

TAN

i i

i

is

q

DirectMSN

is

q

M4

D1

M1M1

D2

D5M4 D2

M2

FS

nAChRD5

D5

M1 M2

LTS

s

is

q

Figure 3Dopaminergic and cholinergic modulation of striatal neurons. Schematic depicting different types of striatalneurons and their complement of dopamine and acetylcholine receptors. Striatopallidal (indirect-pathway)and striatonigral (direct-pathway) MSNs are shown in gray. FS and LTS interneurons are depicted in blueand red, respectively, and the cholinergic neuron is shown in green. G protein–coupled receptors aredisplayed with their associated G-protein: Gs (magenta), Gi ( purple), or Gq (blue). FS interneurons alsoexpress the ionotropic nicotinic ACh receptor.

CONCLUSIONS

Significant heterogeneity exists within both in-terneuron and projection neuron populations inthe striatum. In addition to differences in synap-tic convergence, intrinsic membrane proper-ties, and in vivo firing patterns, each type ofstriatal neuron expresses a distinct comple-ment of DA and ACh receptors (Figure 3).Thus, changes in ACh or DA levels will ex-ert complex effects on striatal neuron activity,as well as on DA and ACh release itself. Forexample, increased dopaminergic tone is pre-dicted to increase D2 receptor activation selec-tively, given its relatively higher affinity for DA(Richfield et al. 1989). This would lead to de-creased striatopallidal MSN output, decreasedcholinergic interneuron activity, and subse-quent reductions in cholinergic tone. However,

reduced autoinhibition of ACh release mightcompensate to some extent for this reductionin cholinergic tone. Reduced depolarization ofFS interneurons via nicotinic receptors wouldalso occur, rendering them less excitable. Simi-larly, reduced activation of presynaptic nicotinicreceptors on dopamine terminals would reduceDA release itself, and the system would reestab-lish an equilibrium level of DA and ACh.

In contrast, brief spikes in DA concentra-tions could exert significantly different effects.Large increases in DA yield both D1 and D2 re-ceptor activation. Thus, striatonigral MSN out-put would be enhanced, whereas striatopallidalMSNs would be inhibited. Excitability of bothFS and LTS interneurons would be increased,yielding more powerful feedforward inhibitionand increased temporal precision of MSN

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spiking output. Cholinergic interneuronswould exhibit more complex changes owing tothe opposing actions of simultaneous D2 andD5 receptor activation. Given the diversityof striatal neurons and their responses tovarious neuromodulators, it is also apparentthat significant caution is required in experi-mental design and data interpretation whenperforming pharmacological manipulations inthe intact striatum.

Interestingly, diseases of the striatum suchas Parkinson disease and Huntington diseaseselectively affect particular neuronal subtypes.Recent evidence indicates that striatopallidalMSNs undergo spine loss following dopaminedepletion, whereas neighboring striatonigralMSNs retain normal morphology (Day et al.2006). At the same time, striatopallidal MSNsexhibit increased firing rates (Mallet et al.2006), which suggests that this decrease inspine density may reflect a compensatory mech-anism aimed at reducing overexcitation. In

Huntington disease, striatopallidal MSNs areselectively vulnerable to cell death (Mitchellet al. 1999, Reiner et al. 1988), although bothtypes of MSNs eventually degenerate. In con-trast, striatal interneurons are selectively spared(Cicchetti et al. 1996, Ferrante et al. 1985).The increased prevalence of interneurons inHuntington disease could exacerbate striataldeficits arising from loss of MSNs (Cepeda et al.2004).

Heterogeneity among neuronal populationsis therefore a critical factor to consider whenstudying striatal function. However, the physi-ological properties of striatal neurons also de-pend on the properties of their synaptic inputs.In addition, a host of other neuromodulatorsincluding adenosine, endocannabinoids, nitricoxide, and various neuropeptides play impor-tant roles in shaping the physiology of striatalneurons. Future studies will be required to un-derstand how these various factors interact toregulate basal ganglia circuit function.

DISCLOSURE STATEMENT

The author is not aware of any affiliations, memberships, funding, or financial holdings that mightbe perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

I thank members of my laboratory for their critical reading of the manuscript and Carlo Tringalefor administrative assistance. Our research on this subject is supported by the Pew CharitableTrusts, the CHDI Foundation, and The J. David Gladstone Institutes.

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Annual Review ofNeuroscience

Volume 32, 2009Contents

Neuropathic Pain: A Maladaptive Response of the NervousSystem to DamageMichael Costigan, Joachim Scholz, and Clifford J. Woolf � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Synaptic Mechanisms for Plasticity in NeocortexDaniel E. Feldman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �33

Neurocognitive Mechanisms in Depression: Implications forTreatmentLuke Clark, Samuel R. Chamberlain, and Barbara J. Sahakian � � � � � � � � � � � � � � � � � � � � � � � � � �57

Using Diffusion Imaging to Study Human Connectional AnatomyHeidi Johansen-Berg and Matthew F.S. Rushworth � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �75

Serotonin in Affective ControlPeter Dayan and Quentin J.M. Huys � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �95

Physiology and Pharmacology of Striatal NeuronsAnatol C. Kreitzer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 127

The Glial Nature of Embryonic and Adult Neural Stem CellsArnold Kriegstein and Arturo Alvarez-Buylla � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 149

Representation of Number in the BrainAndreas Nieder and Stanislas Dehaene � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 185

Neuronal Gamma-Band Synchronization as a Fundamental Processin Cortical ComputationPascal Fries � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 209

The Neurobiology of Individual Differences in ComplexBehavioral TraitsAhmad R. Hariri � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 225

The Science of Neural Interface SystemsNicholas G. Hatsopoulos and John P. Donoghue � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 249

The Neuropsychopharmacology of Fronto-Executive Function:Monoaminergic ModulationT.W. Robbins and A.F.T. Arnsten � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 267

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The Influence of Stress Hormones on Fear CircuitrySarina M. Rodrigues, Joseph E. LeDoux, and Robert M. Sapolsky � � � � � � � � � � � � � � � � � � � � � � � 289

The Primate Cortical Auditory System and Neural Representation ofConspecific VocalizationsLizabeth M. Romanski and Bruno B. Averbeck � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 315

Establishment of Axon-Dendrite Polarity in Developing NeuronsAnthony P. Barnes and Franck Polleux � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 347

Axon Growth and Guidance: Receptor Regulationand Signal TransductionMichael O’Donnell, Rebecca K. Chance, and Greg J. Bashaw � � � � � � � � � � � � � � � � � � � � � � � � � � � � 383

Cerebellum and Nonmotor FunctionPeter L. Strick, Richard P. Dum, and Julie A. Fiez � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 413

Advances in Light Microscopy for NeuroscienceBrian A. Wilt, Laurie D. Burns, Eric Tatt Wei Ho, Kunal K. Ghosh,Eran A. Mukamel, and Mark J. Schnitzer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 435

Indexes

Cumulative Index of Contributing Authors, Volumes 23–32 � � � � � � � � � � � � � � � � � � � � � � � � � � � 507

Cumulative Index of Chapter Titles, Volumes 23–32 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 511

Errata

An online log of corrections to Annual Review of Neuroscience articles may be found athttp://neuro.annualreviews.org/

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Kreitzer Physiology and Pharmacology of Striatal Neurons

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Transcript of Kreitzer Physiology and Pharmacology of Striatal Neurons