We investigated whether fluoxetine, a widely prescribed medication for treatment of depression, restores neuronal plasticity in the adult visual system of the rat. We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders.

Experience-dependent plasticity in the cortex is often higher during short critical periods in postnatal development. The mechanisms limiting adult cortical plasticity are still unclear. Maturation of intracortical GABAergic inhibition is suggested to be crucial for the closure of the critical period for ocular dominance (OD) plasticity in the visual cortex. We find that reduction of GABAergic transmission in the adult rat visual cortex partially reactivates OD plasticity in response to monocular deprivation (MD). This is accompanied by an enhancement of activity-dependent potentiation of synaptic efficacy but not of activity-dependent depression. We also found a decrease in the expression of chondroitin sulfate proteoglycans in the visual cortex of MD animals with reduced inhibition, after the reactivation of OD plasticity. Thus, intracortical inhibition is a crucial limiting factor for the induction of experience-dependent plasticity in the adult visual cortex.

Thus far, the developmental plasticity of the visual system has been studied by altering or reducing visual experience. Here, we investigated whether a complex sensory-motor stimulation, provided by rearing animals in an enriched environment, affects visual system development. We found that raising mice in this condition causes an earlier eye opening, a precocious development of visual acuity, and an accelerated decline of white matter-induced long-term potentiation. These effects are accompanied by a precocious cAMP response element-mediated gene expression and a significant increase of BDNF protein and GAD65/67 expression in enriched pups. In addition, we showed that enriched pups experienced higher levels of licking behavior provided by adult females. Thus, rearing mice from birth in an enriched environment leads to a conspicuous acceleration of visual system development as ascertained at behavioral, electrophysiological, and molecular level.

Environmental enrichment (EE) was shown recently to accelerate brain development in rodents. Increased levels of maternal care, and particularly tactile stimulation through licking and grooming, may represent a key component in the early phases of EE. We hypothesized that enriching the environment in terms of body massage may thus accelerate brain development in infants. We explored the effects of body massage in preterm infants and found that massage accelerates the maturation of electroencephalographic activity and of visual function, in particular visual acuity. In massaged infants, we found higher levels of blood IGF-1. Massage accelerated the maturation of visual function also in rat pups and increased the level of IGF-1 in the cortex. Antagonizing IGF-1 action by means of systemic injections of the IGF-1 antagonist JB1 blocked the effects of massage in rat pups. These results demonstrate that massage has an influence on brain development and in particular on visual development and suggest that its effects are mediated by specific endogenous factors such as IGF-1.

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Total lack of visual experience [dark rearing (DR)] is known to prolong the critical period and delay development of sensory functions in mammalian visual cortex. Recent results show that neurotrophins (NTs) counteract the effects of DR on functional properties of visual cortical cells and exert a strong control on critical period duration. NTs are known to modulate the development and synaptic efficacy of neurotransmitter systems that are affected by DR. However, it is still unknown whether the actions of NTs in dark-reared animals involve interaction with neurotransmitter systems. We have studied the effects of DR on the expression of key molecules in the glutamatergic and GABAergic systems in control and NT-treated animals. We have found that DR reduced the expression of the NMDA receptor 2A subunit and its associated protein PSD-95 (postsynaptic density-95), of GRIP (AMPA glutamate receptor interacting protein), and of the biosynthetic enzyme GAD (glutamic acid decarboxylase). Returning dark-reared animals to light for 2 hr restored normal expression of the above-mentioned proteins almost completely. NT treatment specifically counteracts DR effects; NGF acts primarily on the NMDA system, whereas BDNF acts primarily on the GABAergic system. Finally, the action of NT4 seems to involve both excitatory and inhibitory systems. These data demonstrate that different NTs counteract DR effects by modulating the expression of key molecules of the excitatory and inhibitory neurotransmitter systems.

By acting through retinal nicotinic acetylcholine receptors (nAChRs), acetylcholine plays an important role in the development of both the retina and central visual pathways. Ligand binding and immunoprecipitation studies with subunit-specific antibodies showed that the expression of ␣Bungarotoxin (␣Bgtx) and high-affinity epibatidine (Epi) receptors is regulated developmentally and increases until postnatal day 21 (P21). The increase in Epi receptors is caused by a selective increase in the subtypes containing the ␣2, ␣4, ␣6, ␤2, and ␤3 subunits. Immunopurification studies revealed three major populations of Epi receptors on P21: ␣6* receptors (26%), which contain the ␣6␤3␤2, ␣6␣4␤3␤2, and ␣6␣3/␣2␤3␤2 subtypes; ␣4(non-␣6)* receptors (60%), which contain the ␣2␣4␤2 and ␣4␤2 subtypes; and (non-␣4/non-␣6)* receptors (14%), which contain the ␣2␤2/␤4 and ␣3␤2/␤4 subtypes. These three populations can be pharmacologically discriminated using ␣conotoxin MII, which binds the ␣6* population with high affinity. In situ hybridization showed that the transcripts for all of the subunits are heterogeneously distributed throughout retinal neurons at P21, with ␣3, ␣6, and ␤3 transcripts preferentially concentrated in the ganglion cell layer, ␣5 in the inner nuclear layer, and ␣4 and ␤2 distributed rather homogeneously. To investigate whether nAChR expression is affected by visual experience, we also studied dark-reared P21 rats. Visual deprivation had no effect on the expression of ␣Bgtx receptors or the developmentally regulated Epi receptors containing the ␣2, ␣6, and/or ␤3 subunits but significantly increased the expression of the Epi receptors containing the ␣4 and ␤2 subunits. Overall, this study demonstrates that the retina is the rat neural region that expresses the widest array of nAChR subtypes. These receptors have a specific distribution, and their expression is finely regulated during development and by visual experience.The nicotinic acetylcholine receptors (nAChRs) in vertebrate retina play a role in signaling at the earliest stages of development (long before there is any evidence of synaptic transmission) and also later during neuronal growth and synaptogenesis (Zhou, 2001;Feller, 2002). Neuronal nAChRs are cationic channels whose opening is physiologically controlled by acetylcholine (ACh) neurotransmitter. They form a heterogeneous family of pentameric oligomers made up of combinations of subunits encoded by at least 12 different genes. Although there are many subtypes consisting of different subunits, depending on their phylogenetic, functional, and pharmacological properties (Gotti et al., 1997a;Corringer et al., 2000;Hogg et al., 2003), two main classes have been identified: the ␣Bungarotoxin (␣Bgtx)-sensitive receptors made up of the ␣7, ␣8, ␣9, and/or ␣10 subunits, which can form homomeric or heteromeric receptors; and the ␣Bgtx-insensitive receptors consisting of the ␣2 to ␣6 and ␤2 to ␤4 subunits, which only form heteromeric receptors that bind epibatidine (Epi) with a high affinity. The number ...

neural circuits display a heightened sensitivity to external stimuli during well-established windows in early postnatal life. After the end of these critical periods, brain plasticity dramatically wanes. The visual system is one of the paradigmatic models for studying experiencedependent plasticity. Here we show that food restriction can be used as a strategy to restore plasticity in the adult visual cortex of rats. A short period of food restriction in adulthood is able both to reinstate ocular dominance plasticity and promote recovery from amblyopia. These effects are accompanied by a reduction of intracortical inhibition without modulation of brainderived neurotrophic factor expression or extracellular matrix structure. our results suggest that food restriction could be investigated as a potential way of modulating plasticity.