IAN THOMPSON AXONAL PLASTICITY

Excitement over inhibition

Activity-dependent modulation of axon terminal morphology hals been shown to occur rapidly after brief visual deprivation and also to sculpt inhibitory terminals in the auditory system.

A common feature of the developing mammalian nervous system is that the precise, adult pattern of connections between neural structures emerges from an initially much more diffuse pattern. Various mechanisms are involved in the refinement of the initial connections. One important mechanism is the retraction and consolidation of axon terminals, a process that can be modulated by patterns of neuronal activity. Two recent studies provide new in- sight into this aspecrt of the development of sensory con- nections. Antonini and Stryker [l] report that brief de- privation of vision in one eye leads to a rapid reshap- ing of geniculate axonal arbors in the visual cortex, and Sanes and Takacs [2] show that activity-dependent ter- minal refinement is not restricted to excitatory allerents. Both studies raise interesting questions about the cellu- lar machinery through which patterns of neuronal activity influence arbor morphology.

The monocular deprivation (MD) paradigm, introduced by Wiesel and Hubel, has become one of the key pro- tocols for investigating activity-dependent modulation of neuronal development. In brief, most neurons- in the pri- mary visual cortex of the cat can normally be activated by

visual stimulation through either eye. If, however, visual experience is restricted to just one eye during a ‘critical period lasting a few weeks after eye-opening, then sub- sequently the majority of cortical neurons will respond only to stimulation through that eye, stimulation through the previously deprived eye activating very few neurons. Associated with these physiological changes is an increase in the cortical territory occupied by geniculate terminals receiving input from the stimulated eye and a reduction in the territory occupied by those from the deprived eye 131.

Interestingly, the classic change in ocular dominance seen after prolonged MD can also be obtained by short periods of MD at the height of the critical period (Fig. 1). There is evidence in the literature, however, that the changes seen alter brief MD reflect synaptic suppression of inputs from the deprived eye rather than structural changes in termi- nal distributions. Thus, both Blakemore and Hawken [4] and Freeman and Ohzawa [51, using different techniques, were able to reveal significant functional input from the deprived eye after brief MD. These studies suggested that the consequence of monocular deprivation is an initial,

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Fig. 1. The physiological and anatomical effects of brief MD. The histograms illustrate the relative influence of the two eyes on the population of cortical neurons in normal and in MD animals, redrawn from [Ill. In the histograms, categories 1 to 7 represent patterns of activation by the two eyes. If a neuron is excited equally strongly by the two eyes, it is placed in category 4. If the neuron can be activated only by one eye, it is palced in category 1 or 7 depending on which of the two eyes is effective. If the neuron can be activated by both eyes but one eye is more effective than the other, the neuron is placed in one of the categories 2, 3, 5 or 7, depending on the relative dominance of the two eyes. In normal animals, the majority of neurons can be activated through both non-deprived (ND) eyes - very few neurons are monocular (groups 1 and 7). Brief periods of MD at four weeks of age dramatically shift the balance of cortical ocular dominan$e such that, following deprivation for 8 days, virtually no neurons can be activated through the deprived (D) eye (groups 2-7).

@ Current Biology 1993, Vol 3 No 9

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and potentially reversible, down-regulation of synapses previously activated through the deprived eye, which is then followed by :a retraction of the axon terminals. The paper by Antonini and Stryker [ 11 clearly shows that rapid changes in the morphology of terminal arbors must also contri,$?ute to the physiological effects of brief MD.

The anterograde tracer, phaseolus lectin, was injected intO different layers of the lateral geniculate nucleus to reveal the morphology of geniculate arbors in the visual cortex that are activated by neuronal input from either the de- prived or non-deprived eye. When the morphology of the arbors is reconstructed (Fig. 2), it is clear that the visually deprived arbors are reduced in extent and that the axonal restriction is similar whether the deprivation occurs from birth or merely for 6-7 days at the height of the critical period. The deprived arbors are also smaller than those in age-matched controls - thus, visual deprivation has led to the rapid and active elimination of terminal pro- cesses. Conversely, the arbors serving the non-deprived eye are not significantly larger than control arbors - brief MD appears unable to induce overgrowth of axons as rapidly as it does axonal restriction. (However an anatomi- cal study of primate visual cortex does suggest rapid ter- minal expansion following brief MD, although this was in a reverse-suture paradigm in which first one then the other eye was deprived [6] .> The rapid changes in genic- ulate arbors reported by Antonini and Stryker [l] raise an obvious question: what cellular mechanisms translate imbalances of afferent activity into changes in terminal morphology? In particular, the MD paradigm suggests that some form of comparison, presumably post-synaptic, of activity in the two populations of geniculate afferents is involved, rather than a simple disuse-atrophy of the de- prived terminals. The prediction which follows is that the morphology of geniculate arbors, as determined by phase- olus kin, would be unaffected by a period of binocular deprivation.

elimination of other synapses that are not active at the same time. It has also been suggested that the N-methyl D- aspartate (NMDA) receptor, which is gated both by mem- brane depolarization and excitatory amino-acids, plays an important role in this process. Although such a model can clearly apply to the development of depolarizing, exci- tatory connections, can the same rules apply to the de- velopment of ordered inhibitory connections? A recent paper [2] has examined the development of inhibitory connections, and their dependence on normal activity, in the mammalian auditory pathway.

Sanes and Takks [2] have exploited the beau&l or- ganization of the binaural inputs to the lateral superior olive (ISO), a brainstem auditory nucleus in which in- put from one ear arrives by an excitatory pathway and input from the other ear is inhibitory (Fig. 3a). Individual inhibitory afferents normally convey information about a limited range of auditory frequencies, and their axonal arbors are correspondingly restricted in the axis of the E-0 along which frequency is mapped (Fig. 3a). Remov- ing one cochlea shortly after birth abolishes auditory re- sponses in the inhibitory inputs to the LSO on one side. Thus, the authors were able to compare the morphol- ogy of normal and sensorily deprived inhibitory tierents within one animal. They found that the territory occupied by the deprived-ear aflerents were expanded relative to the normal afferents (Fig. 3b). Examining the terminal arborizations in immature animals revealed that tierent denervation had prevented at least part of the normal process of maturation. As with geniculo-cortical terminals in the visual cortex, the inhibitory inputs to the IS0 are initially diffusely distributed and, under normal conditions, subsequently refine to give a more restricted distribution and so establish a precise tonotopic mapping of inhibition (Fig. 3~). The implication of the Sanes and Takks study is that the process of inhibitory terminal retiement requires functional input from the cochlea.

A common view of the activity-dependent patterning These results from the LSO remind us that the pattern of neuronal connections is based on modifications of of development can be similiar for both inhibitory and Hebbian-learning rules, in which coincident input ac- excitatory projections. But is the cellular basis the same: tivity leads to stabilization of the active synapses and does coincident inhibition stabilize synapses in a similiar

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Fig. 2. Axonal tracing of the genicu- late inputs to visual cortex shows that MD dramatically reduces the arboriza- tion of terminals driven by input from the deprived eye (D terminals) com- pared to those activated by the non- deprived eye (ND terminals) [II. The ar- bor reduction is similar whether the MD was long-term, from before eye-open- ing, or short-term, for a week starting at around five weeks of age. The geniculate arbors are mostly restricted to cortical layer 4.

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Fig. 3. The requirement for normal patterns of activity in the development of the inhibitory input to the lateral superior olive (LSO) 121. (a) A diagrammatic representation of binaural input into the LSO. Sound is transduced in the cochlea and, via the auditory nerve, activates neurons in the cochfear nucleus. The cochlear nucleus makes two projections to the LSO: an excitatory projection to the nucleus on the same side and an inhibitory input, via a synaptic relay in the medial nucleus of the trapezoid body (MNTB), to the opposite LSO. The tonotopic map in the adult LSO is generated by the restricted arborizations of both the excitatory and inhibitory inputs. Ablating the cochlea early in development deprives one set of connections of normal patterns of auditory input. (b) Sample terminal arbors of the inhibitory input from MNTB to LSO in an animal with unilateral cochlea ablation. (The control input is activated by the intact cochlea, whereas the d#enervated input would have been driven by the lesioned cochlea.) The denervated terminals are much more diffusely distributed. fc) The histogram details the spread of axonal terminals (boutons) along the tonotopic axis of that part of the LSO representing high auditory frequencies. Both immature and denervated terminals are more widely spread than adult control terminals suggesting that the normal process of refinement is activity-dependent.

manner to that postulated for excitatory input and, if so, what is the transduction mechanism? Is it significant that the inhibitory input to the IS0 is glycinergic and that ligand binding to the NMDA receptor’s glycine-binding site is a prerequisite for channel opening? The impor- tance of plasticity at inhibitory synapses is also becoming increasingly clear in the adult. Activity-dependent potenti- ation of inhibitory synapses has recently been described in the siphon withdra.wal reflex of 4Zy.d [7] and in the glycinergic input to the goldfish Mauthner cell [S]. Both these studies were al,le to demonstrate that the poten- tiation of inhibition occurred at the inhibitory synapse, rather than via an ‘excitatory-input driving inhibitory in- temeurons. Moreover, in the case of the Mauthner cell input [81, there is evidence that changes in post-synaptic

calcium are important in the potentiation of the inhibitory synapse.

The demonstration of activity-dependent, rapid reline- ment of the morphology of axonal terminals of both excitatory and inhibitory neurons raises many of the same questions associated with long-term potentiation. For instance, what is the relative importance of pre- and post-synaptic mechanisms? It also raises the question of whether the developmental rules determining neuronal morphology and the refinement of connections are largely independent of the neurotransmiuer phenotype. In this context, it is interesting that the trophic influences of the two inputs, excitatory and inhibitory, on the postsynap- tic neurons in the IS0 are different [9,10]: reduction of

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activity in the excitatory input leads to neuronal atrophy whereas reduction in the inhibitory input can produce hypertrophy.

References ..=

1. ANTONINI A, STRYK;ER MP: Rapid remodelling of axonal arbors in the visual cortex. Science1993, 260:1819-1821.

2. SANES DH, T.&&s C: Activity-dependent refinement of inhibitory connections. Em J Neurosci 1993, 5:57&574.

3. SHATZ CJ, STRYICEA: MP: Ocular dominance in layer IV of the cat’s visual cortex and the effects of monocular deprivation. J Pbysiol 1978, 281~267-283.

4. BLUEMORE C, HAWKEN MJ: Rapid restoration of functional input to the visual cortex of the cat after brief monocular depri- vation. J Pkysibl 1982, 327~463-487.

5. FREEMAN RD, OHTAWA I: Monocularly deprived cats: binocular tests of cortical c:eils reveal functional connections from the deprived eye. J Neurosci 1988, 8:2491-2506.

6. S-ALE NV, VIT,U;DURAND F, BLAKEMORE C: Recovery from monocular deprivation in the monkey: III. Reversal of the

anatomical effects in the visual cortex. Proc Roy Sot Land B 1981, 213:435-450.

7. FISCHER TM, CAREW TJ: Activity-dependent potentiation of recurrent inhibition: a mechanism for dynamic gain control in the siphon withdrawal reflex of ApZysiu, J Neurosci 1993, 13:1302-1314.

8. KORN H, ODA Y, FABER DS: Long-term potentiation of inhibitory circuits and synapses in the central nervous system. Proc Nat1 Acud Sci USA 1992, 89~440-443.

9. MOORE D: Trophic intluences of excitatory and inhibitory synapses on neurones in the auditory brainstem. Neuroreport 1992, 3269-272.

10. SANJZS DH, MAFXOWITL S, BERNSTEIN J, WARDLOW J: The influence of inhibitory tierents on the development of postsynaptic dendritic arbors. J Comp New-01 1992, 321:637-644.

11. MOVSHON JA, DWXELER MR: Effects of brief periods of monocular closure on the kitten’s visual system. J Neurop@iol 1977, 40:1255-1265.

Ian Thompson, The University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK.

IN THE: AUGUST 1993 ISSUE OF CURRENT OPINION IN NJXJROBIOLOGY

Randall Reed and Wolf Singer edited the following reviews on Sensory systems:

Olfactory imprinting by Robyn Hudson Visual pathways supporting perception and action in the primate cerebral cortex by Melvyn A Goodale

Early events in auditory processing by James 0. Pickles Genetic determinants of visual function by Samir S. Deeb

Glutamate and GARA in retinal circuitry by Colin J. Barnstable The physiology of vertebrate taste reception by Timothy A. Gilbertson

Learning-induced changes of auditory receptive fields by Norman M. Weinberger A rich complexity emerges in phototransduction by Yiannis Koutalos and King-Wai Yau The biochemistry and molecular biology of taSte transduction by Robert F. Margolskee

The pharmacology of pain signalling by Walter Zieglgtisberger and Thomas R. Tiille Response synchronization in the visual cortex by Ad Aertsen and Martin Arndt

Central core modulation of spontaneous oscillations and sensory transmission in the thalamocortical systems by Mircea Steriade

Audition in echolocating bats by Gerhard Neuweiler and Sabine Schmidt Olfaction in invertebrates by Neelam Shirsat and Obaid Siddiqi

The role of spatio-temporal firing patterns in neuronal development of sensory systems by Rachel O.L. Wong

Central hyperexcitability triggered by noxious inputs by Stephen B. McMahon, Gary R. Lewin and Patrick D. Wall

Synaptic transmission and modulation in the olfactory bulb by Paul Q. Trombley and Gordon M. Shepherd