Maria Spolidoro

Reducing Intracortical Inhibition in the Adult Visual Cortex Promotes Ocular Dominance Plasticity

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.

Brain Plasticity and Disease: A Matter of Inhibition

One major goal in Neuroscience is the development of strategies promoting neural plasticity in the adult central nervous system, when functional recovery from brain disease and injury is limited. New evidence has underscored a pivotal role for cortical inhibitory circuitries in regulating plasticity both during development and in adulthood. This paper summarizes recent findings showing that the inhibition-excitation balance controls adult brain plasticity and is at the core of the pathogenesis of neurodevelopmental disorders like autism, Down syndrome, and Rett syndrome.

Serotonin triggers a transient epigenetic mechanism that reinstates adult visual cortex plasticity in rats

Cortical circuitries are highly sensitive to experience during early life but this phase of heightened plasticity decreases with development. We recently demonstrated that fluoxetine reinstates a juvenile‐like form of plasticity in the adult visual system. Here we explored cellular and molecular mechanisms that underlie the occurrence of these plastic phenomena. Adult rats were intracortically treated with serotonin (5‐HT) whereas long‐term fluoxetine‐treated rats were infused with the 5‐HT1A‐receptor antagonist WAY‐100635, brain‐derived neurotrophic factor (BDNF) scavenger trkB‐IgG or the mitogen‐activated protein kinase inhibitor U0126. Plasticity was assessed as variations of visual cortex responsiveness after unilateral eyelid suture and reverse occlusion by using an electrophysiological approach. Real‐time PCR and chromatin immunoprecipitation analysis were then used to explore alterations in gene expression and modifications of chromatin structure associated with the plastic outcome caused by fluoxetine in the visual system. Local infusion of 5‐HT into visual cortex restored susceptibility to monocular deprivation in adulthood whereas infusion of WAY‐100635, trkB‐IgG or U0126 prevented the process of plasticity reactivation in fluoxetine‐treated animals. Long‐term fluoxetine treatment promoted a transient increase of Bdnf expression in the visual cortex, which was paralleled by an increased histone acetylation status at Bdnf promoter regions and by decreased expression of Hdac5. Accordingly, enhancing histone acetylation levels by systemic treatment with Trichostatin‐A reactivated plasticity in the adult while WAY‐100635‐infusion prevented epigenetic modifications in Bdnf promoter areas. The data suggest a key role for 5‐HT1A receptor and BDNF‐trkB signalling in driving a transitory epigenetic remodelling of chromatin structure that underlies the reactivation of plasticity in the visual system.

Plasticity in the adult brain: lessons from the visual system

While cortical circuits display maximal sensitivity to sensory experience during critical periods of early postnatal development, far less plasticity is present in the mature brain. Ocular dominance shift of visual cortical neurons in response to eye occlusion and recovery of visual functions from a period of sensory deprivation are two classical models in the study of critical period determinants in the visual cortex. Recent papers employing various pharmacological and environmental strategies have shown that it is possible to reinstate much greater levels of plasticity in the adult visual cortex than previously suspected. These studies point toward intracortical inhibition as a crucial determinant for critical period regulation in the visual system and have a great potential for therapeutic rehabilitation and recovery from injury in the adult brain.

Cerebellum involvement in cortical sensorimotor circuits for the control of voluntary movements.

Sensorimotor integration is crucial to perception and motor control. How and where this process takes place in the brain is still largely unknown. Here we analyze the cerebellar contribution to sensorimotor integration in the whisker system of mice. We identify an area in the cerebellum where cortical sensory and motor inputs converge at the cellular level. Optogenetic stimulation of this area affects thalamic and motor cortex activity, alters parameters of ongoing movements and thereby modifies qualitatively and quantitatively touch events against surrounding objects. These results shed light on the cerebellum as an active component of sensorimotor circuits and show the importance of sensorimotor cortico-cerebellar loops in the fine control of voluntary movements.

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

Brain cells are immersed in a complex structure forming the extracellular matrix. The composition of the matrix gradually matures during postnatal development, as the brain circuitry reaches its adult form. The fully developed extracellular environment stabilizes neuronal connectivity and decreases cortical plasticity as highlighted by the demonstration that treatments degrading the matrix are able to restore synaptic plasticity in the adult brain. The mechanisms through which the matrix inhibits cortical plasticity are not fully clarified. Here we show that a prominent component of the matrix, chondroitin sulfate proteoglycans (CSPGs), restrains morphological changes of dendritic spines in the visual cortex of adult mice. By means of in vivo and in vitro two-photon imaging and electrophysiology, we find that after enzymatic digestion of CSPGs, cortical spines become more motile and express a larger degree of structural and functional plasticity.

GABAergic inhibition in visual cortical plasticity.

Experience is required for the shaping and refinement of developing neural circuits during well defined periods of early postnatal development called critical periods. Many studies in the visual cortex have shown that intracortical GABAergic circuitry plays a crucial role in defining the time course of the critical period for ocular dominance plasticity. With the end of the critical period, neural plasticity wanes and recovery from the effects of visual defects on visual acuity (amblyopia) or binocularity is much reduced or absent. Recent results pointed out that intracortical inhibition is a fundamental limiting factor for adult cortical plasticity and that its reduction by means of different pharmacological and environmental strategies makes it possible to greatly enhance plasticity in the adult visual cortex, promoting ocular dominance plasticity and recovery from amblyopia. Here we focus on the role of intracortical GABAergic circuitry in controlling both developmental and adult cortical plasticity. We shall also discuss the potential clinical application of these findings to neurological disorders in which synaptic plasticity is compromised because of excessive intracortical inhibition.

Food restriction enhances visual cortex plasticity in adulthood.

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 experience-dependent 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 brain-derived neurotrophic factor expression or extracellular matrix structure. Our results suggest that food restriction could be investigated as a potential way of modulating plasticity.

α-synuclein assemblies sequester neuronal α3-Na+/K+-ATPase and impair Na+ gradient

Extracellular α‐synuclein (α‐syn) assemblies can be up‐taken by neurons; however, their interaction with the plasma membrane and proteins has not been studied specifically. Here we demonstrate that α‐syn assemblies form clusters within the plasma membrane of neurons. Using a proteomic‐based approach, we identify the α3‐subunit of Na+/K+‐ATPase (NKA) as a cell surface partner of α‐syn assemblies. The interaction strength depended on the state of α‐syn, fibrils being the strongest, oligomers weak, and monomers none. Mutations within the neuron‐specific α3‐subunit are linked to rapid‐onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). We show that freely diffusing α3‐NKA are trapped within α‐syn clusters resulting in α3‐NKA redistribution and formation of larger nanoclusters. This creates regions within the plasma membrane with reduced local densities of α3‐NKA, thereby decreasing the efficiency of Na+ extrusion following stimulus. Thus, interactions of α3‐NKA with extracellular α‐syn assemblies reduce its pumping activity as its mutations in RDP/AHC.

Activation of Rho GTPases Triggers Structural Remodeling and Functional Plasticity in the Adult Rat Visual Cortex

A classical example of age-dependent plasticity is ocular dominance (OD) plasticity, triggered by monocular deprivation (MD). Sensitivity of cortical circuits to a brief period of MD is maximal in juvenile animals and downregulated in adult age. It remains unclear whether a reduced potential for morphological remodeling underlies this downregulation of physiological plasticity in adulthood. Here we have tested whether stimulation of structural rearrangements is effective in promoting experience-dependent plasticity in adult age. We have exploited a bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), that regulates actin dynamics and structure of neuronal processes via a persistent activation of Rho GTPases. Injection of CNF1 into the adult rat visual cortex triggered a long-lasting activation of the Rho GTPase Rac1, with a consequent increase in spine density and length in pyramidal neurons. Adult rats treated with CNF1, but not controls, showed an OD shift toward the open eye after MD. CNF1-mediated OD plasticity was selectively attributable to the enhancement of open-eye responses, whereas closed-eye inputs were unaffected. This effect correlated with an increased density of geniculocortical terminals in layer IV of monocularly deprived, CNF1-treated rats. Thus, Rho GTPase activation reinstates OD plasticity in the adult cortex via the potentiation of more active inputs from the open eye. These data establish a direct link between structural remodeling and functional plasticity and demonstrate a role for Rho GTPases in brain plasticity in vivo. The plasticizing effects of Rho GTPase activation may be exploited to promote brain repair.