Conflicts in the pharmacology of visual cortical plasticity

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Conflicts in the pharmacology of visual cortical plasticity There is a clearly defined time in early life, the so-called 'critical period', during which it is possible to provoke major changes in the functional connectivity of the visual cortex 1'2. The limitation of this cortical plasticity to such a specific time domain lends itself to the idea that it may reflect the influence of a relatively discrete process. Indeed it appeared that such a process may have been identified when Kasamatsu and Pettigrew 3 reported that intraventricular injections of 6hydroxydopamine (6-OHDA), a neurotoxin believed to be selective for catecholaminergic cells in the CNS when applied in micromolar concentrations, depleted cortical noradrenaline levels and produced a loss of plasticity within the critical period in kittens. This and subsequent work from their laboratory3-7 led to the hypothesis that plasticity within the critical period is secondary to some form of heightened influence of the noradrenergic input from the locus coeruleus. It is perhaps not surprising that these claims have provoked considerable controversy, but what is remarkable in relation to this issue is that evidence apparently favouring the involvement of noradrenaline in plasticity has been accumulating at the same time as contrary evidence showing that depletion of the noradrenergic input to the visual cortex has no effect on plasticity during the critical period. The primary model for all the work in this area has been the shift in the ocular dominance of cells in the kitten visual cortex following a period of monocular deprivation. In the normal visual cortex, the majority of neurones have input from both eyes and roughly equal proportions are dominated by each eye, but after monocular deprivation in the critical period (between three weeks and three months postnatal), virtually all cells respond only to the nondeprived eye 1'2"8. Deprivation outside the critical period is without effect. Using the deprivation paradigm there is common agreement that direct intracortical microinfusion of 6-OHDA can block the shift in ocular dominance in animals within the critical period 5,9,1°. Conversely it now seems clear that depletion of cortical noradrenaline per se, as achieved by a variety of methods

including intraventricular injection of 6-OHDA, does not block the shift in ocular dominance H-13. Further to these studies, Daw et al. 14 have recently shown that intraventricular injection of a neurotoxin, DSP-4, rather more selective for central noradrenergic endings, although producing a marked depletion of cortical noradrenaline levels, had no effect on plasticity. This suggests that where effective, it is some facet of the action of 6-OHDA other than its influence on noradrenergic terminals that blocks the plasticity. One possibilityis a non-specific disruption of cortical activity, an idea supported by the report that infusion of glutamate directly into the cortex will also block plasticityis. The effects of glutamate could either be secondary to a generalized elevation in the activity of cortical cells or a consequence of its neurotoxic effects. Certainly high concentrations of 6-OHDA are likely to cause non-selective damage in the neocortex, and one is left with the view that any process that causes a severe disruption of the normal functioning of the neocortex may affect the conditions essential to plasticity within the critical period. This is reinforced by experiments showing that other types of lesion, such as destruction of the medial thalamic complex, or disruption of the input from the extraocular eye muscles, also limit visual cortical plasticity16"17. The apparent paradox in all this is the claim ofPettigrew, Kasamatsu and their colleagues that either microperfusion of the visual cortex with noradrenaline or electrical stimulation of the locus coeruleus can restore some plasticity in animals outside the critical period4'6'7'18. Assuming that this finding will be broadly substantiated in a number of other laboratories, does it prove that plasticity within the critical period is primarily precipitated by the action of the noradrenergic input? I would suggest that given the data discussed in the preceding paragraph it does not. What it does indicate is that noradrenaline may influence a process important to plasticity, which may also be influenced by other agents. The noradrenergic input to the neocortex may influence both metabolism and neuronal responsiveness19'2°. Whereas evidence suggests that it increases

metabolism, its predominant effect on cortical neurones appears to be inhibitory, which is also the case for electrical stimulation of the locus coeruleus. However, there is evidence from the hippocampus to suggest that, in addition to its hyperpolarizing action, noradrenaline exerts an influence on the calcium-dependent potassium channel 21, which if applicable to the neocortex would be commensurate with an enhancement of stimulus-elicited excitatory responses. How might these various facets of the influence of noradrenaline relate to plasticity within the critical period? One possibility is that the plasticity requires an enhanced level of cortical metabolic activity and that this can be produced by microperfusion with noradrenaline. Other modulatory inputs to the cortex, including the serotonergic input 19, may influence metabolism, and it is possible that a deficit in one could be compensated for by the others, hence the disassociation between noradrenaline levels and plasticity. In this context it is significant that the density and laminar distribution of serotonergic fibres in the developing monkey visual cortex suggest a closer correlation with ocular dominance plasticity than the noradrenergic input 22. Alternatively, considering direct effects of noradrenaline on neuronal activityor responsiveness, it could, via either a reduction in background activity, or enhanced excitatory responses,increasethe contrast between conditions in which the cell was driven by a specific input and those in which it was not. If this type of 'gating, influence', modifying the responsiveness of cortical cells to their normal input, is a critical factor, then it is again clear that other neurotransmitter systems influencing the cortex could have a similar action23. For example, there is now good evidence to suggest that the cholinergicinput to the visual cortex can markedly enhance the stimulus-driven responses of visual cortical cells by a mechanism that may be inferred to include an action on both the potassium channel subserving the 'M' current and the calcium-dependent potassium channel 24. In a very recent report, Bear and Singer25 describe a series of elegant experiments in which they find that

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302 lesions to either the cholinergic or the noradrenergic input to the cortex have no significant effect on plasticity in the kitten visual cortex, but lesions to both inputs cause a significant loss. What is most interesting in their data is the suggestion that 6-OHDA blocks the facilitatory effects of acetylchofine in the visual cortex, raising the possibility that 6-OHDA appfication to the cortex will in fact block both noradrenergic and cholinergic modulation of cortical activity. Thus, although 6-OHDA microinjection into the cortex may block plasticity via a range of nonspecific effects, the action can be economically explained in terms of a simultaneous suppression of noradrenergic and cholinergic influences. This makes it slightly surprising that perfusion of the mature visual cortex with noradrenaline alone should be capable of restoring plasticity, unless it simply serves to exceed some threshold established by the background influence of the endogenous release of noradrenaline and acetylcholine. Further to this, if the actions of noradrenaline and acetylcholine on plasticity are secondary to an enhanced responsiveness of cortical cells following an inhibition of potassium channels, one would anticipate the cholinergic input to be more important because the facilitatory effects of ACh in the visual cortex are much more prominent than those of noradrenaline2°'24. Thus an enhancement of cholinergic processes in the adult might be expected to have a greater effect on plasticity than microperfusion with noradrenaline. This

Fig. 1. The ocular dominance histograms shown here illustrate the effect of the various procedures discussed in the text on the ocular dominance distribution in the visual cortex. Each histogram shows the relative number o f visual cortical neurones seen in each o f seven ocular dominance categories, where '1" represents cells dominated exclusively by the contralateral eye, '7' represents cells exclusively dominated by the ipsilateral eye, and '4' represents cells equally driven by both eyes. (A) The ocular dominance distribution in the normal adult cat visual cortex, where most cells are binocularly driven. (B) The ocular dominance distribution in a cat monocularly deprived during the critical period. (C) The ocular dominance distribution seen foUowing monocular deprivation within the critical period but with micorperfusion of the visual cortex with 6-OHDA. (D) a s for (C) but with microinfusion with glutamate rather than 6-OHDA. (E) The ocular dominance distribution following monocular deprivation during the critical period and intraventricular injection of DSP-4, which depletes noradrenaline to levels similar to those seen following 6-OHDA infusion.

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must be tested, but it is notable that in Bear and Singer's work 25 lesions to the cholinergic input were as ineffective as those to the noradrenergic. Another question concerns the fact that 6OHDA application exerts positive effects when the eyelids are sutured after 6-OHDA infusion has stopped. Under these circumstances 6-OHDA is not available to block the effects of acetylcholine, and hence it is not clear that Bear and Singer's explanation of the action of 6-OHDA covers the situation as well as it might seem on first reading. When considering the confusing array of data now available, it is necessary to be aware of the potential difficulties in extrapolating from what on first sight may appear to be relatively clear observations. One problem concorns the deprivation paradigms. Contralateral eyelid suture within the critical period tends to produce stronger effects than ipsflateral eyefid suture, and not all authors have proper controls for this in their experimental protocols. Another issue concerns the specificity of effects in the most general sense. Both intravenous and intraventricular drug applications can influence a wide range of processes other than those within the visual cortex and can precipitate a marked deterioration in the health of the animals. Electrical stimulation of the locus coeruleus will exert effects on most of the nervous system. These may be direct or via actions on other groups of neurones, including those involved in the other modulatory inputs. The fact that in these stimulation experiments, Kasamatsu et al. TM failed to observe any evidence for a shift in ocular dominance in animals where the cortex was directly microperfused with 6-OHDA, does not control for specificity, it merely reaffirms the undisputed fact that this procedure will block plasticity. The main issue is that it blocks plasticity in a way that is apparently unrelated to the levels of noradrenaline, and hence it cannot say anything about the mode of action of the stimulation of the locus coeruleus. The main question is whether we have gathered any real insight into the mechanisms generating plasticity within the critical period. The bulk of the available data only shows that disruption of processes central to the normal functioning of the visual cortex also disrupt plasticity. This is hardly surprising and does not constitute an explanation of the events precipitating

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plasticity. It is i m p o r t a n t to r e m e m b e r that all the modulatory inputs to the cortex, including the noradrenergic and cholinergic, play a role in the functioning of the normal adult c o r t e x . Consequently the d e m o n s t r a t i o n of a special role in plasticity requires evidence of a n influence in the critical period that differs in some significant way from that which pertains in adult life. T h e r e is as yet no substantive evidence to favour such a view for either the noradrenergic input or the cholinergic input. The suggestion that there is an increase in the n u m b e r of 13adrenoreceptors within the critical period 26 has not b e e n substantiated by o t h e r workers 27 and hence must remain' open to question at present. If one pursues the a r g u m e n t that the noradrenergic and cholinergic inputs are i m p o r t a n t because of the way they can modulate the response of a cortical cell to its excitatory input via an action on potassium channels, it is difficult to reconcile with the fact that they do this in the adult cortex, which does not exhibit changes in connectivity in response to monocular deprivation. Similar c o m m e n t s apply to potential influences of these systems on metabolism or even cortical blood flow. Judged from this viewpoint, the claim that microperfusion with noradrenaline can restore a small element of plasticity to the m a t u r e cortex is interesting but

not necessarily central to the issue of plasticity within the critical period. If the modulatory inputs to the visual cortex do have a primary role to play in this plasticity, it seems appropriate to look for a variation in the sensitivity of a cellular process, possibly at the level of second messengers, commonly affected by all of them. Acknowledgements

I am most grateful to P. C. Murphy for reading the manuscript and providing many helpful comments. Selected references 1 Wiesel, T. N. and Hubel, D.H. (1963) J. Neurophysiol. 26, 1503-1517 2 Hubel, D. H. and Wiesel. T.N. (1970) J. Physiol. (London) 206, 419-436 3 Kasamatsu, T. and Pettigrew, J. D. (1976) Science 194, 206-208

4 Pettigrew, J. D. and Kasamatsu, T. (1978) Nature 271,761-763 5 Kasamatsu, T. and Petfigrew, J. D. (1979) J. Comp. Neurol. 185, 139-162 6 Kasamatsu,T., Pettigrew, J. D. and Arey, M. (1979) J. Comp. Neurol. 185, 163-182 7 Kasamatsu, T., Penigrew, J. D. and Arey, M. (1981) J. Neurophysiol. 45,254-266 8 Sherman, S. M. and Spear, P.D. (1982) Physiol. Rev. 62, 738--855 9 Paradiso, M. A., Bear, M. F. and Daniels, J. D. (1983) Exp. Brain Res. 51,413-422 10 Daw, N.W.,Rader, R. K.,Robertson,T. W. and Ariel, M. (1983)J. Neurosci. 3, 907-914 11 Bear, M. F. and Daniels, J.D. (1983) J. Neurosci. 3, 407-416

12 Adrien, J. P., Buis~ret, Y., Fregnac, Y., Oary-Bobo, E., Imbert, M., Tassin, J. P. and Trotter, Y. (1982) C. R. Acad. Sci. Set. D. 295,745-750 13 Daw, N. W., Robertson, T.W., Radcr, R. K.,Videen,T. O.andCo~ia, C. J.(1984) J. Neurosci. 4, 1354-1360 14 Daw, N. W., Videen, T. O., Parkinson, D. and Raider, R.K. (1985) J. Neurosci. 5, 1925-1933 15 Shaw, C. and Cynader, M. (1984)Nature 308, 731-734 16 Freeman, R. D. and Bonds, A. B. (1979) Science 206, 1093-1095 17 Singer, W. (1982)Exp. BrainRes. 47,2219-222 18 Kasamatsu, T., Watabe, K., Heggelund, P. and Scholler, E. (1985) Neurosci. Res. 2, 365-386 19 Magistretti, P. J. and Schorderet, M. (1985) J. Neurosci. 5, 362-368

20 Videen, T. O., Daw, N. W. and Rader, R. K. (1984) J. Neurosci. 4, 1607-1617 21 Madison, D. V. and Nicoll, R. A. (1986) J. Physiol. (London) 372, 221-244 22 Foote, S. L. and Morrison, J.H. (1984) J. Neurosci. 4, 2667-2680

23 Sillito, A. M. (1983) Nature 303, 477-478 24 Sillito, A. M. and Kemp, J. A. (1983) Brain Res. 289, 143-155 25 Bear, M. F. and Singer, W. Nature (in press) 26 Jonsson, G. and Kasamatsu, T. (1983) Exp. Brain Res. 50, 449-458 27 Shaw, C. N., Eedler, M. C., Wilkinson, M., Aoki, C. and Cynader, M. (1984) Prog. Neurso-psychopharmacol. Biol. Psychiatr. 8,

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A. M. SILLITO Department of Physiology, University College, PO Box 78, Cardiff CFI IXL, UK.