What's critical for the critical period in visual cortex?

A recent paper in Cell, using a very different genetic approach, also arrived at the conclusion that GABAergic circuits are critically involved in regulating the critical period. In contrast to Hensch et al. 1998axHensch, T.K, Fagiolini, M, Mataga, N, Stryker, M.P, Baekkeskov, S, and Kash, S.F. Science. 1998; 282: 1504–1508Crossref | PubMedSee all ReferencesHensch et al. 1998a, howeverHuang et al. 1999xHuang, Z, Kirkwood, A, Pizzorusso, T, Porciatti, V, Morales, B, Bear, M, Maffei, L, and Tonegawa, S. Cell. 1999; 98: 739–755Abstract | Full Text | Full Text PDF | PubMed | Scopus (660)See all ReferencesHuang et al. 1999 conclude that a genetic manipulation that enhances inhibition leads to a reduced capacity for cortical plasticity, and actually results in premature closure of the critical period. To achieve thisHuang et al. 1999xHuang, Z, Kirkwood, A, Pizzorusso, T, Porciatti, V, Morales, B, Bear, M, Maffei, L, and Tonegawa, S. Cell. 1999; 98: 739–755Abstract | Full Text | Full Text PDF | PubMed | Scopus (660)See all ReferencesHuang et al. 1999 created a transgenic mouse in which the gene for a neurotrophin, brain-derived neurotrophic factor (BDNF), was placed under the control of the αCAMKII promoter, which effectively restricted BDNF overexpression to excitatory neocortical neurons.BDNF and other neurotrophins have been strongly implicated in ocular dominance column formation and plasticity. Such findings have been interpreted primarily in the light of a neurotrophic theory based on the activity-dependent release of neurotrophins from postsynaptic cells (see above). In this scheme, adding excess of BDNF should eliminate the advantages of correlated activity, since sufficient neurotrophin would be accessible to all presynaptic terminals, correlated or not. The transgenic mice of Huang et al. 1999xHuang, Z, Kirkwood, A, Pizzorusso, T, Porciatti, V, Morales, B, Bear, M, Maffei, L, and Tonegawa, S. Cell. 1999; 98: 739–755Abstract | Full Text | Full Text PDF | PubMed | Scopus (660)See all ReferencesHuang et al. 1999 suggest a quite different role and mechanism for BDNF. Rather than acting as a retrograde signal for correlation-based competition, BDNF may regulate maturation of a crucial component of cortical circuitry, the inhibitory interneurons. This may in turn change the “set point” at which neurons are able to detect changes in patterns of incoming activity.Unlike excitatory neurons, inhibitory neurons do not normally synthesize BDNF; however, they express abundant receptors for BDNF and in culture respond strongly to exogenous BDNF (Marty et al. 1996xMarty, S, Carroll, P, Cellerino, A, Castren, E, Staiger, V, Thoenen, H, and Lindholm, D. J. Neurosci. 1996; 16: 675–687PubMedSee all ReferencesMarty et al. 1996). In wild-type mice, anatomical and electrophysiological markers of inhibition reach adult levels by postnatal day 35, near the close of the critical period in mice (which ends at about postnatal day [PND] 32). By a variety of anatomical and electrophysiological criteria, overexpression of BDNF in excitatory neurons accelerated the development of inhibitory neurons and inhibitory synaptic connections throughout the visual cortex, such that animals as young as PND 21 already showed adult-like inhibitory circuits. The fascinating correlate to this premature development is that monocular deprivation at PND 28—the height of the critical period in wild-type mice—had almost no effect in the BDNF transgenics. In these animals, the critical period seemed to close almost a week earlier than normal. Unlike most prior pharmacological or genetic manipulations, BDNF overexpression did not simply prevent plastic changes—monocular deprivation earlier in the critical period still could elicit robust shifts in ocularity. At one level, these results contrast strongly with those of Hensch et al. 1998axHensch, T.K, Fagiolini, M, Mataga, N, Stryker, M.P, Baekkeskov, S, and Kash, S.F. Science. 1998; 282: 1504–1508Crossref | PubMedSee all ReferencesHensch et al. 1998a, who found that an apparent decrease in cortical inhibition led to loss of plasticity, with no effect on LTP or LTD. Huang et al. 1999xHuang, Z, Kirkwood, A, Pizzorusso, T, Porciatti, V, Morales, B, Bear, M, Maffei, L, and Tonegawa, S. Cell. 1999; 98: 739–755Abstract | Full Text | Full Text PDF | PubMed | Scopus (660)See all ReferencesHuang et al. 1999, on the other hand, find that an apparent increase in inhibition leads to a loss of plasticity, and that this effect on ocular dominance plasticity correlates well with effects on LTP. What are we to make of this discrepancy?First, there are obvious limitations both to the mouse model and the methodology of probing ocular dominance shifts that are common to both investigations. In cats, ferrets, and monkeys, a well-defined, unambigious anatomical change in the pattern of thalamic afferents in layer 4 accompanies the physiological shifts in eye preference: thalamic terminals representing the open eye expand, while those representing the closed eye shrink (Figure 1BFigure 1B). However, as the critical period wanes, and stretching much later into juvenile life, substantial eye preference shifts outside of layer 4 can occur even in the absence of the reorganization of thalamic afferents (LeVay et al. 1980xLeVay, S, Wiesel, T.N, and Hubel, D.H. J. Comp. Neurol. 1980; 191: 1–51Crossref | PubMedSee all ReferencesLeVay et al. 1980). Indeed, raising animals in complete darkness—a manipulation that allegedly prolongs the critical period—exerts its effects primarily on cortical local circuits, as segregation of thalamic afferents in layer 4 remains intact in these animals (Mower et al. 1985xMower, G.D, Caplan, C.J, Christen, W.G, and Duffy, F.H. J. Comp. Neurol. 1985; 235: 448–466CrossrefSee all ReferencesMower et al. 1985). Physiological reorganization outside layer 4 clearly involves different circuits and mechanisms than those that mediate the “classic” critical period. In mice, the anatomical correlates of eye preference shifts are less dramatic (although clearly observable) (Antonini et al. 1999xAntonini, A, Fagiolini, M, and Stryker, M.P. J. Neurosci. 1999; 19: 4388–4406PubMedSee all ReferencesAntonini et al. 1999), and neither the single-unit electrophysiology nor the visual evoked potentials used in these two studies discriminate between cortical layers. Conceivably some of these results (and some of the discrepancy between them) could be explained by mechanisms not involving layer 4 at all.From another standpoint, however, it may not be as surprising that both raising and lowering inhibitory tone can decrease plasticity. Recent findings in cultured cortical neurons indicate that cortical neurons regulate their excitability so as to maintain a sort of synaptic homeostasis (Turrigiano et al. 1998xTurrigiano, G.G, Leslie, K.R, Desai, N.S, Rutherford, L.C, and Nelson, S.B. Nature. 1998; 391: 892–896Crossref | PubMed | Scopus (1096)See all ReferencesTurrigiano et al. 1998). Thus, if neurons are receiving less inhibition (as in the GAD65 knockout mice) the strength of excitatory synapses would be expected to decrease; if they are receiving more inhibition (as in the BDNF overexpressing mice) the strength of excitatory inputs might also increase. Indeed, there is evidence in culture that when activity is blocked, BDNF acts to decrease the size of excitatory inputs onto pyramidal cells and increase the size of excitatory inputs onto inhibitory cells (Rutherford et al. 1998xRutherford, L.C, Nelson, S.B, and Turrigiano, G.G. Neuron. 1998; 21: 521–530Abstract | Full Text | Full Text PDF | PubMed | Scopus (304)See all ReferencesRutherford et al. 1998). If this two-pronged approach also occurred in vivo, it would substantially reduce the excitability of the cortical circuit. Such circuit-level alterations in excitability could prevent detection or interpretation of activity differences between inputs from the two eyes. Although extrapolation 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 failure 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. 1999xLein, E, Finney, E, McQuillen, P, and Shatz, C. Proc. Natl. Acad. Sci. USA. 1999; in pressSee all ReferencesLein 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 circuits involved in this phenomenon. More optimistically, the fact that direct manipulation of inhibition can remove, delay, or restore the ability of the circuit to be modified provides a fresh avenue for thinking about the critical period; and the ability to use genetic approaches to accomplish these manipulations in identified cell types, and at specific times, offers the promise of rigorously dissecting the contributions of specific cells and circuits.