Molecular Basis Of Plasticity In The Visual Cortex

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ReviewTRENDS in Neurosciences Vol.26 No.7 July 2003369Molecular basis of plasticity in thevisual cortexNicoletta Berardi1,2, Tommaso Pizzorusso1,3, Gian Michele Ratto1 andLamberto Maffei1,31Laboratory of Neurophysiology, Istituto di Neuroscienze, Pisa, ItalyDepartment of Psychology, University of Florence, Florence, Italy3Laboratory of Neurobiology, Scuola Normale Superiore, Pisa, Italy2Sensory experience is known to shape the maturationof cortical circuits during development. A paradigmaticexample is the effect of monocular deprivation on ocular dominance of visual cortical neurons. Althoughvisual cortical plasticity has been widely studied sinceits initial discovery by Hubel and Wiesel 40 years ago,the description of the underlying molecular mechanisms has lagged behind. Several new findings are nowbeginning to close this gap. Recent data deepen ourknowledge of the factors involved in the intercellularcommunication and intracellular signaling that mediateexperience-dependent plasticity in the developingvisual cortex. In addition, new findings suggest a rolefor the extracellular matrix in inhibition of ocular-dominance plasticity in the adult visual cortex.Development of the visual cortex is strongly influenced byvisual experience during short periods of postnataldevelopment called critical periods. During these periodsof heightened plasticity, experience can produce permanent and extensive modifications of cortical organization.If during the critical period one eye is deprived ofpatterned vision, as is the case following unilateralcongenital cataract or experimental monocular deprivation, there is an irreversible reduction of visually drivenactivity in the visual cortex through the deprived eye,which is reflected by a dramatic shift in the oculardominance distribution of cortical neurons in favour of thenon-deprived eye in all mammals tested [1,2]. Followingmonocular deprivation, visual acuity and contrast sensitivity for the deprived eye (tested either behaviourally orelectrophysiologically) develop poorly (amblyopia) andthere is a loss of depth perception. Similar effects can beproduced by abnormal alignment of the two eyes (strabismus). The loss of depth perception has been directlyrelated to the loss of binocular cells in the visual cortex,whereas the loss of visual acuity has been attributed bothto the total decrease of neurons driven by the deprived eyeand to a loss of those neurons with the smallest receptivefields [3]. It has to be said that abnormalities in thedominance of the deprived eye and in the spatial propertiesof visual cortical neurons alone do not explain the fullrange of visual deficits in amblyopia [3], and thatCorresponding author: Lamberto Maffei ([email protected]).ocular-dominance plasticity and development of visionmight be based on different cellular mechanisms [4,5].However, there seems to be a close link between criticalperiod duration and maturation of some visual functions:for instance, the closure of the critical period for monoculardeprivation roughly coincides with completion of visualacuity development in several species, including rodents,monkeys and humans [1], suggesting that the development of visual function and the progressive reduction ofocular-dominance plasticity are two aspects of the sameprocess – namely, the maturation of the visual cortex.Experience shapes the development and maintenanceof visual cortical circuits through activity-dependentmechanisms that seem to follow Hebb’s principle, ahypothesis first put forth to explain ocular-dominanceplasticity but then extended to explain experience-dependent development of other visual functions. Hebb’sprinciple states that if electrical activity in a set of afferentfibers is temporally correlated with the activity of thepostsynaptic neuron, then the afferents will be allowed tomaintain and even expand the connections with it.However, if the activity is not temporally correlated, theafferent fibers will loose their hold on the postsynapticneuron.Plasticity in the visual cortex declines with age. Adultvisual cortex still responds to experience with plasticchanges, as shown by the effects of perceptual learning [6]and of retinal lesions [7], with similar Hebbian rulesgoverning these changes as are in force during criticalperiods. However, the extent of plasticity is reduced in theadult with respect to the young: monocular deprivation orstrabismus in adults produce no effect, and recovery fromamblyopia is also very limited once the critical period isterminated.The cellular and molecular mechanisms that control thedevelopmental plasticity of visual cortical connections andrestrict experience-dependent plasticity to short criticalperiods are still unclear. This article reviews recentadvances in this field.NMDA receptorsThe first modifications induced by experience in visualcortical circuits are likely to be changes in synaptic efficacy.Ever since the discovery of NMDA receptors, these synapticreceptors have been implicated in experience-dependenthttp://tins.trends.com 0166-2236/03/ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0166-2236(03)00168-1

370ReviewTRENDS in Neurosciences Vol.26 No.7 July 2003plasticity. Their characteristic of being both transmitterand voltage-dependent, and their coupling via Ca2þ influxto plasticity-related intracellular signalling, has led to thenotion that they might be a neural implementation ofHebbian synapses.Involvement of NMDA receptors in developmentalvisual cortical plasticity has been initially suggested bythe observation that block of NMDA receptors blocks theeffects of monocular deprivation [8]. A difficulty withpharmacological block of NMDA receptors can be that itsignificantly affects visually driven activity, but the use ofdifferent NMDA receptor antagonists [9] or antisenseoligonucleotides to reduce expression of the NMDAR1subunit has overcome this problem, showing that it ispossible to block the effects of monocular deprivationwithout affecting visual responses [10] and confirmingNMDA-receptor involvement in visual cortical plasticity.NMDA receptors are developmentally regulated andtheir expression is modified by electrical activity. Inparticular, their subunit composition varies in the visualcortex, from a dominant presence of receptors containingthe subunit 2B to a high presence of receptors containingthe subunit 2A, with a time course paralleling that offunctional visual cortical development and the criticalperiod. Expression of the 2A subunit correlates with theprogressive shortening of NMDA current. Dark rearing,which delays critical-period closure and impairs development of functional properties of the visual cortex and ofvisual acuity, delays the developmental shortening ofNMDA-receptor currents and of subunit 2A expression,suggesting that the 2B-to-2A switch is related to visualcortical development and, possibly, to the closure of thecritical period [1].However, recent results have shown that in mice withdeletion of the NMDA-receptor 2A subunit, the sensitivityto monocular deprivation is restricted to the normalcritical period, thus suggesting that expression of the 2Asubunit is not essential to delineate the time course of thecritical period of ocular-dominance plasticity [5] and mightbe related to other features of visual cortical plasticity.NeurotrophinsSeveral observations have suggested that neurotrophinscontrol visual cortical plasticity during the critical period.Initially, it was shown that exogenous supply of neurotrophins in the visual cortex strongly affects the oculardominance plasticity induced by monocular deprivation[1,11]. In these studies, the effects of neurotrophins onocular dominance plasticity were sometimes accompaniedby alteration of other properties of visual cortical neurons,such as their pattern of discharge and orientationselectivity [12,13], possibly owing to the high concentration of exogenous neurotrophins. Other studies, whichfollowed the opposite course of antagonizing the action ofendogenous neurotrophins, have clearly shown thatneurotrophins are important for normal visual corticaldevelopment and plasticity [14,15]. More recently, Huanget al. [16] generated a mouse overexpressing brain-derivedneurotrophic factor (BDNF) in the visual cortex, maintaining a normal cellular pattern of BDNF expression andrelease. In this mouse, BDNF overexpression accelerateshttp://tins.trends.comboth the development of visual acuity and the time courseof ocular dominance and synaptic plasticity, thus supporting a crucial role for neurotrophins in visual corticaldevelopment and plasticity.What are the mechanisms of action of neurotrophins incontrolling experience-dependent visual cortical plasticity? Neurotrophin production and release depend onelectrical activity and, in particular, depend on visualactivity [11]. In turn, neurotrophins can modulate electrical activity and synaptic transmission at both presynaptic and postsynaptic levels [17,18]. They can have bothfast actions, for instance by increasing transmitter release[19,20] or by directly depolarizing neurons [21], and slowactions, by modulating gene expression [18] (Fig. 1a,b).BDNF also enhances visual cortical synaptic plasticity[11]. This reciprocal regulation between neurotrophinsand neural activity might provide a means by which activeneuronal connections are selectively strengthened.Indeed, neurotrophins seem to require the presence ofelectrical activity to exert their actions [11,19,22].Recently, Konnerth and colleagues have demonstratedthat the coincidence between weak synaptic activity andlocalized BDNF application, which by themselves do notlead to long lasting changes in synaptic efficacy, induceslong-lasting potentiation of synaptic transmission,suggesting that neurotrophins operate in synergy withelectrical activity in promoting synaptic plasticity [23]. Itis interesting to note that, although BDNF can promotethe phosphorylation of the transcription factor cAMPresponse-element-binding protein (CREB) (Fig. 2), itevokes only weak CREB-mediated gene expression unlessit is coupled with electrical activity [24].Several studies on neurotrophin-receptor expressionand on the effects of neurotrophins on visual corticalneurons or afferents to the visual cortex have indicatedthat different neurotrophins act on different neuronaltargets [11]. Therefore, the synergy between neurotrophins and activity has to be considered to be specific foreach neurotrophin and the neuronal populations that areits targets. The possible sites of action of neurotrophins invisual cortical plasticity are illustrated in Fig. 1c.A strong link between BDNF and intracortical inhibition has been recently suggested by the finding thatdevelopment of intracortical GABA-mediated inhibition isaccelerated in BDNF-overexpressing mice [16], suggestingthat BDNF controls the time course of the critical period byaccelerating the maturation of GABA-mediated inhibition(Box 1).A final consideration is necessary. The local supply ofneurotrophins has been proposed as possible therapy forneurological and neurodegenerative diseases. The cleardemonstration that neurotrophins so strongly affectcortical plasticity and can disrupt activity of corticalneurons warns that their supply could elicit as yetunpredictable side effects, as has been recently pointedout by Thoenen [25].Intracortical inhibitionRecently, it has become clear that inhibition not only is a‘brake’ for excitation but also has an important role insculpting the pattern of electrical activity. This action

Review371TRENDS in Neurosciences Vol.26 No.7 July 2003(a)Effect of activity on NTproduction and releaseEffect of NT on activityand gene expressionNT moleculesNTsNTs(b)Direct excitation Transmitter(BDNF)releaseNTsActivityActivation of pathwaysrelated to induction ofsynaptic plasticityActivation of late,plasticity-related ical neuronGABA?5-HTtrkA?trkBThalamic DNFNT4TRENDS in NeurosciencesFig. 1. Neurotrophin action in visual cortical plasticity. (a) Production and release of neurotrophins (NTs) is under the control of electrical activity (red bars representingaction potentials): a more active afferent (left) would activate more effectively the postsynaptic neuron, therefore evoking a stronger release of neurotrophins. The reversewould be true for less active afferents (right). Released neurotrophins exert then their actions on the presynaptic neuron, in synergy with activity. The specificity of neurotrophin action is determined by the fact that the released neurotrophins exert their actions only on neurons that are active. The less active neuron not only evokes a smallerrelease of neurotrophins but also has a weaker action exerted on it by the released neurotrophins. Neurotrophins can also be released by the presynaptic neuron and acton the postsynaptic neuron, again in synergy with activity. (b) Schematic time scale of neurotrophin actions. No distinction is made between presynaptic or postsynapticsites of action. The scheme suggests that neurotrophins and activity act in synergy in producing several effects, some of which are very fast and some of which are slower.Direct excitation of the postsynaptic neuron has been described for brain-derived neurotrophic factor (BDNF) in several types of cortical neurons. Also for BDNF, however,the induction of synaptic plasticity requires coincidence with activity. Based on Refs [1,18– 23]. (c) Possible targets of neurotrophin actions in the control of visual corticalplasticity. Neurotrophins seem to play their roles by acting on different targets: each neurotrophin has a particular subset of targets among the intracortical neurons andthe cortical afferents. Neurotrophin 4 (NT4) but not BDNF regulates lateral geniculate nucleus soma size [94,95]; BDNF but not nerve growth f