What's Critical for the Minireview Critical Period in Visual Cortex?

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provided by Elsevier - Publisher Connector Cell, Vol. 99, 673–676, December 23, 1999, Copyright 1999 by Cell Press What’s Critical for the Minireview Critical Period in Visual Cortex?

Lawrence C. Katz adults had virtually no effect. Subsequent anatomical Howard Hughes Medical Institute and tracing revealed that the imbalance of activity resulted Department of Neurobiology in the actual loss of synaptic inputs from the thalamic Duke University Medical Center regions representing the closed eye, and expansion of Durham, North Carolina 27710 those representing the open eye (Figure 1B). While in normal primates and cats, the thalamic inputs representing the two eyes parse cortical layer 4 into alternating, During a brief period in postnatal life, sensory experi- equal-sized stripes, eye closure during the critical period ences indelibly shape the behavior of many vertebrate reduced the cortical territory of the closed eye to species. Salmon learn their natal rivers, birds learn their shrunken broken stripes, with its former territory now father’s songs, and humans acquire language based invaded by inputs representing the other eye (Hubel et on particular sensory experiences during such “critical al., 1977). Behaviorally, animals monocularly deprived periods.” Early ethological investigations of critical periods focused on the behavioral consequences of early sensory experiences, but how and where such experiences were permanently etched into brain circuits was unknown. The notion that critical periods actually repre- sented heightened epochs of brain plasticity, and that experience could produce permanent, large-scale changes in neuronal circuits emerged from Hubel and Wiesel’s investigations in the cat and monkey visual cortex begin- ning in the mid-1960s (Hubel and Wiesel, 1970). Despite over three decades of subsequent experimentation, passionate disagreement remains over the cellular and molecular mechanisms initiating and eventually termi- nating this brief period of remarkable plasticity. For years, the battle was waged using pharmacological manipulations in the visual system of cats and primates. Recently, however, genetic manipulations in the mouse have emerged as a powerful new tool for dissecting the molecular underpinnings of critical periods. Two recent reports, using very different genetic manipulations, highlight the development of inhibitory circuitry as a potent modulator of the critical period, although in the best tradition of this contentious area, they reach rather different conclusions. In one case transgenic overexpression of a neurotrophin has made it possible, for the first time, to prematurely close the critical period (Huang et al., 1999); in another other case, critical period plasticity was disrupted in a knockout mouse and subsequently restored with a specific pharmacological agent Figure 1. The Visual Systems of Cat and Mouse and Their Re- (Hensch et al., 1998a). Both the findings themselves sponses to Monocular Deprivation during the Critical Period and the mice engineered to obtain them offer a wealth In cats (and primates) the projections from the ipsilateral (red) and of new opportunities to delve more precisely into the contralateral (green) portions of the two retinas segregate into ana- molecular mechanisms regulating this unique time in tomically discrete layers in the visual thalamus (LGN). LGN neurons vertebrate brain development. from each layer project in turn to segregated zones in layer 4 of In their classic work, Hubel and Wiesel discovered primary visual cortex, forming alternating bands that comprise the that neurons in cat primary visual cortex were activated anatomical basis of ocular dominance columns. In contrast, mice to different degrees by visual stimuli presented to one have a much smaller projection from the ipsilateral retina, and the projections from the two eyes do not form distinct layers in the eye or the other, a property they termed ocular domi- LGN or segregated bands in cortex. In cats, eye closure of the nance. They then made the striking discovery that clos- contralateral eye (indicated the shading in [B]) causes the thalamic ing one eye during the first few months of life led to the afferents to the cortex representing that eye to shrink, while the lifelong, irreversible loss of visually driven activity in the afferents representing the open eye expand. In mice, more subtle cortex through the closed eye, and a dramatic increase changes in individual axon arbors have been observed. Physiologi- in the number of neurons responding best to stimuli cally (C) most cells are activated to some extent by both eyes in presented to the open eye (Figure 1C) (Hubel and Wiesel, normal animals (left histograms); eye closure at the height of the critical period results in a dramatic loss of neurons reponsive to 1970). This was all the more remarkable because re- the closed eye. This shift is somewhat more dramatic in cats and sponses in the deprived retina and thalamus remained monkeys than in mice, but qualitatively similar. (Figure is modified completely unaffected. In contrast to the profound ef- from Wiesel and Hubel, 1970 and earlier references therein, and fects in young animals, even prolonged eye closure in Gordon and Stryker, 1996.) Cell 674

during the critical period are blind in the deprived eye, neurotrophins have potent effects on dendritic and axo- and no amount of subsequent experience can reverse nal growth and synaptic strength, the idea that the struc- the effects of early deprivation. These anatomical and tural and functional effects of deprivation during the behavioral findings are satisfyingly consistent with the critical period could be mediated by these molecules is initial physiological observations that monocular depri- attractive. In its simplest form, the “neurotrophic hypoth- vation leads to a loss of responsiveness through the esis” applied to critical period posits that thalamic affer- closed eye (Figure 1C). Ocular dominance plasticity dur- ents compete, on the basis of activity patterns, for a ing the critical period is clearly based on the relative limited supply of growth factor present in postsynaptic levels and patterns of activity driven by the two eyes, layer 4 cells of the visual cortex. More active inputs and it was recognized early on that the functional and (such as those from the open eye) increase the local structural rearrangements were consistent with some production and release of trophic factors, resulting in sort of correlation rule: the more effective one set of stronger synapses and enhanced axonal sprouting at inputs (such as those from the open eye) were at activat- the expense of the less active inputs from the deprived ing cortical cells, the stronger and more numerous such eye, which get less and therefore atrophy (see, for exam- connections would become, conversely, a less effective ple, Carmignoto et al., 1993). Neurotrophins, especially set of inputs (from the closed eye, for example) would brain-derived neurotrophic factor (BDNF) are present in weaken and eventually disappear. Despite the near uni- the visual cortex at the right time (Allendoerfer et al., versal consensus on the effects of monocular depriva- 1994), and manipulating exogenous or endogenous tion, how such activity differences are actually trans- BDNF levels prevents ocular dominance columns from lated into structural and functional changes in visual forming (Cabelli et al., 1997 and earlier references cortex, and why this only occurs during such a restricted therein). There are, however, recent findings that ques- period of postnatal life, remain unknown. tion this simple model of neurotrophin action: if the cor- Molecular Correlates of the Critical Period tex is pharmacologically silenced, more active afferents The first serious attempt at a molecular explanation for shrink and less active ones remain unchanged, which the timing of the critical period for monocular deprivation cannot be readily explained by the simple model out- was advanced by Pettigrew and Kasamatsu who, in the lined above (Hata et al., 1999). mid-1970s noted that the extent of adrenergic innerva- The Move to Mice tion of cat primary visual cortex paralleled the timing Links between any of these molecules and mechanisms of the critical period. Depleting cortical norepinephrine that control the critical period remain controversial. One with pharmacological agents applied via osmotic mini- of the difficulties facing this field is manipulating candi- pumps apparently prevented the effects of monocular date molecular pathways in a controlled and reproduc- deprivation (Kasamatsu and Pettigrew, 1976), and addi- ible manner. Infusion of drugs or molecules by osmotic tion of norepinephrine after the close of the critical pe- minipumps, for example, leads to radically different con- riod was later claimed to restore plasticity. Despite the centrations at different distances from the infusion site. considerable initial appeal of these findings, a series There is an obvious appeal to use genetic manipulations of subsequent manipulations by Nigel Daw’s lab that to target putative mediators of cortical plasticity. De- depleted cortical norepinephrine failed to show similar spite their rather poorly developed visual cortex, mice effects on plasticity, and, following a considerable pe- have a small zone of binocular visual cortex in which riod of contention, the consensus view was that norepi- individual neurons show the physiological property of nephrine alone was unlikely to be the “plasticizing” mol- ocular dominance (Figures 1A 1C). And in mice, as in ecule of the developing cortex. cats and monkeys, eye closure during a restricted criti- Subsequently, other plausible candidate molecules cal period, from about 21 days to 32 days postnatal, have been implicated. The discovery of the NMDA re- results in a pronounced, competition-based shift in receptor and its central role in the induction of hippocam- sponsiveness toward the open eye (Gordon and Stryker, pal long-term potentiation (LTP) and depression (LTD) 1996). Mice do not have the obvious anatomical basis prompted a flurry of investigations into whether similar of ocular dominance—segregated thalamic afferents in mechanisms were responsible for translating the effects layer 4—and consequently eye closure does not lead to of differential visual experience into structural and func- the same sort of wholesale changes in the organization tional changes. Such mechanisms are intrinsically ap- of thalamic afferents seen in cats and monkeys, al- pealing, as the effects of monocular deprivation involve though changes in individual afferents are readily ob- one set of synapses getting stronger (an LTP-like effect) served (Antonini et al., 1999) (Figure 1B). and another set getting weaker (an LTD-like effect). LTP One initial motivation for exploring knockout mice was and LTD clearly occur in visual and other cortical areas to determine whether LTP (and its companion, LTD) are during (and after) the critical period, pharmacological in fact required for critical period plasticity. According agents that block LTP and LTD prevent the physiological to this reasoning, genetic manipulations that either en- effects of eye closure, and manipulations of experience hance or prevent LTP should have predictable effects that alter critical period (such as dark rearing) have con- on critical period plasticity; dissonance would imply that sistent effects on certain aspects of LTP (see, for exam- LTP is not necessary for plastic rearrangements to oc- ple, Kirkwood et al., 1995 and earlier references therein). cur. For example, mice expressing a defective form of Several other lines of research have focused attention protein kinase A (PKA) lack some forms of cortical LTP on the neurotrophin family of growth factors. As the level and LTD; nevertheless, they exhibit robust ocular domi- of expression of neurotrophins in visual cortex can be nance shifts in response to monocular deprivation regulated by visual stimulation (Castren et al., 1992) and (Hensch et al., 1998b). Minireview 675

Inhibition and Control of the Critical Period Neurotrophins, Inhibition, and Regulation From work in cortical and hippocampal brain slices, it’s of the Critical Period well known that pharmacologically lowering levels of A recent paper in Cell, using a very different genetic inhibition (by application of GABAA receptor antagonists, approach, also arrived at the conclusion that GABAergic for example) lowers the threshold for eliciting LTP. In circuits are critically involved in regulating the critical cortical brain slices, for example, LTP can be readily period. In contrast to Hensch et al. (1998a), however, elicited in the upper cortical layers by white matter stim- Huang et al. (1999) conclude that a genetic manipulation ulation in young animals, but only by stimulation of corti- that enhances inhibition leads to a reduced capacity cal layer 4 in adult animals. However, reducing the level for cortical plasticity, and actually results in premature of inhibition pharmacologically enables LTP to be elic- closure of the critical period. To achieve this, Huang et ited by white matter activation even in adults. This has al. (1999) created a transgenic mouse in which the gene led to the notion that inhibitory circuits in layer 4 act as for a neurotrophin, brain-derived neurotrophic factor a “gate” for synaptic modifications during critical period (BDNF), was placed under the control of the ␣CAMKII (Kirkwood and Bear, 1994): early on, inhibition is weak, promoter, which effectively restricted BDNF overex- the gate is open, and synaptic modifications occur, sub- pression to excitatory neocortical neurons. sequently, the development of inhibitory circuits in layer BDNF and other neurotrophins have been strongly 4 closes the gate, preventing synaptic modifications implicated in ocular dominance column formation and from occurring. If LTP and ocular dominance plasticity plasticity. Such findings have been interpreted primarily during the critical period are in fact tightly linked, one in the light of a neurotrophic theory based on the activity- might expect that global reductions in inhibition would dependent release of neurotrophins from postsynaptic both enhance cortical LTP and either prolong the critical cells (see above). In this scheme, adding excess of BDNF period or enhance the effects of monocular deprivation should eliminate the advantages of correlated activity, during the critical period. since sufficient neurotrophin would be accessible to all presynaptic terminals, correlated or not. The transgenic For at least one knockout mouse, this does not appear mice of Huang et al. (1999) suggest a quite different to be the case. Normal mice have two isoforms of glu- role and mechanism for BDNF. Rather than acting as tamic acid decarboxylase (GAD). GAD67, the primary a retrograde signal for correlation-based competition, synthetic enzyme, is localized to cell bodies; its deletion BDNF may regulate maturation of a crucial component causes death at birth. The other isoform, GAD65, is of cortical circuitry, the inhibitory interneurons. This may localized to synaptic terminals, and GAD65 knockout in turn change the “set point” at which neurons are able mice are superficially normal. However, during the criti- to detect changes in patterns of incoming activity. cal period, both overall GABA levels, and the amounts Unlike excitatory neurons, inhibitory neurons do not released by stimulation, are markedly reduced. Although normally synthesize BDNF; however, they express abun- the cortex is not epileptic (as occurs when inhibition is dant receptors for BDNF and in culture respond strongly totally eliminated) neurons in these mice show pro- to exogenous BDNF (Marty et al., 1996). In wild-type longed responses to visual stimuli, suggesting that the mice, anatomical and electrophysiological markers of inhibitory circuits are less effective. Hensch et al. inhibition reach adult levels by postnatal day 35, near (1998a) found that these GAD65 knockout mice showed the close of the critical period in mice (which ends at no shift in physiologically measured ocular dominance about postnatal day [PND] 32). By a variety of anatomical preference when one eye was closed during the critical and electrophysiological criteria, overexpression of period. Despite the absence of a deprivation-induced BDNF in excitatory neurons accelerated the develop- shift during the critical period, these animals had appar- ment of inhibitory neurons and inhibitory synaptic con- ently normal LTP and LTD, demonstrating that the ma- nections throughout the visual cortex, such that animals chinery for detecting Hebbian-like correlations was as young as PND 21 already showed adult-like inhibitory functional. The critical observation, however, is that a circuits. The fascinating correlate to this premature de- loss of cortical plasticity was not accompanied by a velopment is that monocular deprivation at PND 28—the concomitant loss of LTP and/or LTD, implying that these height of the critical period in wild-type mice—had al- two phenomena are, to some extent at least, separable. most no effect in the BDNF transgenics. In these ani- Remarkably, locally infusing diazepam—a use-depen- mals, the critical period seemed to close almost a week dent GABA agonist—restored the ability of neurons to earlier than normal. Unlike most prior pharmacological undergo an ocular dominance shift in response to eye or genetic manipulations, BDNF overexpression did not closure. The fact that a knockout mouse has a deficit simply prevent plastic changes—monocular deprivation in plasticity does not, in itself, provide any great insight earlier in the critical period still could elicit robust shifts into mechanisms—mucking with enzymes could have in ocularity. At one level, these results contrast strongly all sorts of uninterpretable sequelae. But the ability to with those of Hensch et al. (1998a), who found that an restore plasticity with a specific pharmacological agent apparent decrease in cortical inhibition led to loss of strongly suggests that the deficit in plasticity is a proxi- plasticity, with no effect on LTP or LTD. Huang et al. mal effect of the gene deletion itself, rather than an (1999), on the other hand, find that an apparent increase indirect side effect. This observation is also not easily in inhibition leads to a loss of plasticity, and that this reconciled with a central role of LTP in ocular shifts, effect on ocular dominance plasticity correlates well as increased inhibitory tone should have reduced, not with effects on LTP. What are we to make of this dis- augmented, the ability of stimuli to elicit this form of crepancy? synaptic plasticity. First, there are obvious limitations both to the mouse Cell 676

model and the methodology of probing ocular domi- circuits involved in this phenomenon. More optimisti- nance shifts that are common to both investigations. In cally, the fact that direct manipulation of inhibition can cats, ferrets, and monkeys, a well-defined, unambigious remove, delay, or restore the ability of the circuit to be anatomical change in the pattern of thalamic afferents modified provides a fresh avenue for thinking about the in layer 4 accompanies the physiological shifts in eye critical period; and the ability to use genetic approaches preference: thalamic terminals representing the open to accomplish these manipulations in identified cell eye expand, while those representing the closed eye types, and at specific times, offers the promise of rigor- shrink (Figure 1B). However, as the critical period wanes, ously dissecting the contributions of specific cells and and stretching much later into juvenile life, substantial circuits. eye preference shifts outside of layer 4 can occur even in the absence of the reorganization of thalamic afferents Selected Reading (LeVay et al., 1980). Indeed, raising animals in complete Allendoerfer, K.L., Cabelli, R.J., Escandon, E., Kaplan, D.R., Nikolics, darkness—a manipulation that allegedly prolongs the K., and Shatz, C.J. (1994). J. Neurosci. 14, 1795–1811. critical period—exerts its effects primarily on cortical Antonini, A., Fagiolini, M., and Stryker, M.P. (1999). J. Neurosci. 19, local circuits, as segregation of thalamic afferents in 4388–4406. layer 4 remains intact in these animals (Mower et al., Cabelli, R.J., Shelton, D.L., Segal, R.A., and Shatz, C.J. (1997). Neu- 1985). Physiological reorganization outside layer 4 clearly ron 19, 63–76. involves different circuits and mechanisms than those Carmignoto, G., Canella, R., Candeo, P., Comelli, M.C., and Maffei, that mediate the “classic” critical period. In mice, the L. (1993). J. Physiol. 464, 343–360. anatomical correlates of eye preference shifts are less Castren, E., Zafra, F., Thoenen, H., and Lindholm, D. (1992). Proc. dramatic (although clearly observable) (Antonini et al., Natl. Acad. Sci. USA 89, 9444–9448. 1999), and neither the single-unit electrophysiology nor Gordon, J.A., and Stryker, M.P. (1996). J. Neurosci. 16, 3274–3286. the visual evoked potentials used in these two studies Hata, Y., Tsumoto, T., and Stryker, M.P. (1999). Neuron 22, 375–381. discriminate between cortical layers. Conceivably some Hensch, T.K., Fagiolini, M., Mataga, N., Stryker, M.P., Baekkeskov, of these results (and some of the discrepancy between S., and Kash, S.F. (1998a). Science 282, 1504–1508. them) could be explained by mechanisms not involving Hensch, T.K., Gordon, J.A., Brandon, E.P., McKnight, G.S., Idzerda, layer 4 at all. R.L., and Stryker, M.P. (1998b). J. Neurosci. 18, 2108–2117. From another standpoint, however, it may not be as Huang, Z., Kirkwood, A., Pizzorusso, T., Porciatti, V., Morales, B., surprising that both raising and lowering inhibitory tone Bear, M., Maffei, L., and Tonegawa, S. (1999). Cell 98, 739–755. can decrease plasticity. Recent findings in cultured cor- Hubel, D.H., and Wiesel, T.N. (1970). J. Physiol. 206, 419–436. tical neurons indicate that cortical neurons regulate their Hubel, D.H., Wiesel, T.N., and LeVay, S. (1977). Phil. Trans. R. Soc. excitability so as to maintain a sort of synaptic homeo- London (B) 278, 377–409. stasis (Turrigiano et al., 1998). Thus, if neurons are re- Kasamatsu, T., and Pettigrew, J.D. (1976). Science 194, 206–209. ceiving less inhibition (as in the GAD65 knockout mice) Kirkwood, A., and Bear, M.F. (1994). J. Neurosci. 14, 1634–1645. the strength of excitatory synapses would be expected Kirkwood, A., Lee, H.K., and Bear, M.F. (1995). Nature 375, 328–331. to decrease; if they are receiving more inhibition (as in Lein, E., Finney, E., McQuillen, P., and Shatz, C. (1999). Proc. Natl. the BDNF overexpressing mice) the strength of excit- Acad. Sci. USA, in press. atory inputs might also increase. Indeed, there is evi- LeVay, S., Wiesel, T.N., and Hubel, D.H. (1980). J. Comp. Neurol. dence in culture that when activity is blocked, BDNF acts 191, 1–51. to decrease the size of excitatory inputs onto pyramidal Marty, S., Carroll, P., Cellerino, A., Castren, E., Staiger, V., Thoenen, cells and increase the size of excitatory inputs onto H., and Lindholm, D. (1996). J. Neurosci. 16, 675–687. inhibitory cells (Rutherford et al., 1998). If this two- Mower, G.D., Caplan, C.J., Christen, W.G., and Duffy, F.H. (1985). pronged approach also occurred in vivo, it would sub- J. Comp. Neurol. 235, 448–466. stantially reduce the excitability of the cortical circuit. Rutherford, L.C., Nelson, S.B., and Turrigiano, G.G. (1998). Neuron Such circuit-level alterations in excitability could prevent 21, 521–530. detection or interpretation of activity differences be- Turrigiano, G.G., Leslie, K.R., Desai, N.S., Rutherford, L.C., and Nel- tween inputs from the two eyes. Although extrapolation son, S.B. (1998). Nature 391, 892–896. from the behavior of neonatal dissociated neurons in vitro to intact circuits in vivo must be done cautiously, circuit-level regulation of plasticity provides a new way of interpreting—or even predicting—manipulations that augment or block plasticity during the critical period. Indeed, recent work in which one circuit element— subplate neurons—was selectively ablated caused fail- ure of columns to form, accompanied by augmentation of both BDNF and an increase in GAD67 message, consistent with an effect on inhibitory tone (Lein et al., 1999). Clearly our understanding of the cellular and molecular basis of this (or any) critical period remains dim. One discouraging possibility is that any manipulation that disturbs some delicate balance in the cortical circuit may indirectly disrupt the key mechanisms responsible for plastic changes, leading, in the worst case, to an ever-increasing list of candidate molecules, genes, and