Chiara Cerri

AP2gamma regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex.

An important feature of the cerebral cortex is its layered organization, which is modulated in an area-specific manner. We found that the transcription factor AP2γ regulates laminar fate in a region-specific manner. Deletion of AP2γ (also known as Tcfap2c) during development resulted in a specific reduction of upper layer neurons in the occipital cortex, leading to impaired function and enhanced plasticity of the adult visual cortex. AP2γ functions in apical progenitors, and its absence resulted in mis-specification of basal progenitors in the occipital cortex at the time at which upper layer neurons were generated. AP2γ directly regulated the basal progenitor fate determinants Math3 (also known as Neurod4) and Tbr2, and its overexpression promoted the generation of layer II/III neurons in a time- and region-specific manner. Thus, AP2γ acts as a regulator of basal progenitor fate, linking regional and laminar specification in the mouse developing cerebral cortex.

Early depolarizing GABA controls critical-period plasticity in the rat visual cortex

Hyperpolarizing and inhibitory GABA regulates critical periods for plasticity in sensory cortices. Here we examine the role of early, depolarizing GABA in the control of plasticity mechanisms. We report that brief interference with depolarizing GABA during early development prolonged critical-period plasticity in visual cortical circuits without affecting the overall development of the visual system. The effects on plasticity were accompanied by dampened inhibitory neurotransmission, downregulation of brain-derived neurotrophic factor (BDNF) expression and reduced density of extracellular matrix perineuronal nets. Early interference with depolarizing GABA decreased perinatal BDNF signaling, and a pharmacological increase of BDNF signaling during GABA interference rescued the effects on plasticity and its regulators later in life. We conclude that depolarizing GABA exerts a long-lasting, selective modulation of plasticity of cortical circuits by a strong crosstalk with BDNF.

Functional Masking of Deprived Eye Responses by Callosal Input during Ocular Dominance Plasticity

Monocular deprivation (MD) is a well-known paradigm of experience-dependent plasticity in which cortical neurons exhibit a shift of ocular dominance (OD) toward the open eye. The mechanisms underlying this form of plasticity are incompletely understood. Here we demonstrate the involvement of callosal connections in the synaptic modifications occurring during MD. Rats at the peak of the critical period were deprived for 7 days, resulting in the expected OD shift toward the open eye. Acute microinjection of the activity blocker muscimol into the visual cortex contralateral to the recording site restored binocularity of cortical cells. Continuous silencing of callosal input throughout the period of MD also resulted in substantial attenuation of the OD shift. Blockade of interhemispheric communication selectively enhanced deprived eye responses with no effect on open eye-driven activity. We conclude that callosal inputs play a key role in functional weakening of less active connections during OD plasticity.

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.

Experience‐dependent expression of NPAS4 regulates plasticity in adult visual cortex

•  Transcription factors at the basis of plasticity in the adult visual system are unknown. •  Enhanced levels of NPAS4 transcription factor parallel visual cortical plasticity in adult life. •  Overexpression of NPAS4 restores plasticity in the adult visual cortex. •  NPAS4 down‐regulation prevents the plastic outcome caused by fluoxetine (FLX) in adulthood. •  NPAS4 regulates the expression of plasticity genes in the adult visual cortex.

Callosal contribution to ocular dominance in rat primary visual cortex

Ocular dominance (OD) plasticity triggered by monocular eyelid suture is a classic paradigm for studying experience‐dependent changes in neural connectivity. Recently, rodents have become the most popular model for studies of OD plasticity. It is therefore important to determine how OD is determined in the rodent primary visual cortex. In particular, cortical cells receive considerable inputs from the contralateral hemisphere via callosal axons, but the role of these connections in controlling eye preference remains controversial. Here we have examined the role of callosal connections in binocularity of the visual cortex in naïve young rats. We recorded cortical responses evoked by stimulation of each eye before and after acute silencing, via stereotaxic tetrodotoxin (TTX) injection, of the lateral geniculate nucleus ipsilateral to the recording site. This protocol allowed us to isolate visual responses transmitted via the corpus callosum. Cortical binocularity was assessed by visual evoked potential (VEP) and single‐unit recordings. We found that acute silencing of afferent geniculocortical input produced a very significant reduction in the contralateral‐to‐ipsilateral (C/I) VEP ratio, and a marked shift towards the ipsilateral eye in the OD distribution of cortical cells. Analysis of absolute strength of each eye indicated a dramatic decrease in contralateral eye responses following TTX, while those of the ipsilateral eye were reduced but maintained a more evident input. We conclude that callosal connections contribute to normal OD mainly by carrying visual input from the ipsilateral eye. These data have important implications for the interpretation of OD plasticity following alterations of visual experience.

The Chemokine CCL2 Mediates the Seizure-enhancing Effects of Systemic Inflammation.

Epilepsy is a chronic disorder characterized by spontaneous recurrent seizures. Brain inflammation is increasingly recognized as a critical factor for seizure precipitation, but the molecular mediators of such proconvulsant effects are only partly understood. The chemokine CCL2 is one of the most elevated inflammatory mediators in patients with pharmacoresistent epilepsy, but its contribution to seizure generation remains unexplored. Here, we show, for the first time, a crucial role for CCL2 and its receptor CCR2 in seizure control. We imposed a systemic inflammatory challenge via lipopolysaccharide (LPS) administration in mice with mesial temporal lobe epilepsy. We found that LPS dramatically increased seizure frequency and upregulated the expression of many inflammatory proteins, including CCL2. To test the proconvulsant role of CCL2, we administered systemically either a CCL2 transcription inhibitor (bindarit) or a selective antagonist of the CCR2 receptor (RS102895). We found that interference with CCL2 signaling potently suppressed LPS-induced seizures. Intracerebral administration of anti-CCL2 antibodies also abrogated LPS-mediated seizure enhancement in chronically epileptic animals. Our results reveal that CCL2 is a key mediator in the molecular pathways that link peripheral inflammation with neuronal hyperexcitability. SIGNIFICANCE STATEMENT Substantial evidence points to a role for inflammation in epilepsy, but currently there is little insight as to how inflammatory pathways impact on seizure generation. Here, we examine the molecular mediators linking peripheral inflammation with seizure susceptibility in mice with mesial temporal lobe epilepsy. We show that a systemic inflammatory challenge via lipopolysaccharide administration potently enhances seizure frequency and upregulates the expression of the chemokine CCL2. Remarkably, selective pharmacological interference with CCL2 or its receptor CCR2 suppresses lipopolysaccharide-induced seizure enhancement. Thus, CCL2/CCR2 signaling plays a key role in linking systemic inflammation with seizure susceptibility.

Visual callosal connections: role in visual processing in health and disease

Abstract Visual cortical areas in the two sides of the brain are interconnected by interhemispheric fibers passing through the splenium of the corpus callosum. In this review, we summarize data concerning the anatomical features of visual callosal connections, their roles in basic visual processing, and how their alterations contribute to visual deficits in different human neuropathologies. Splenial fibers represent a population of excitatory axons with varying diameters, which interconnect cortical columns with similar functional properties (i.e., same orientation selectivity) in the two hemispheres. Their branches activate simultaneously distinct iso-oriented columns in the contralateral hemisphere, thus mediating forms of stimulus-dependent interhemispheric synchronization. Callosal branches also make synapses onto GABAergic cells, resulting in an inhibitory modulation of visual processing that involves both iso-oriented and cross-oriented cortical networks. Interhemispheric inhibition appears to predominate at short latencies following callosal activation, whereas excitation becomes more robust with increasing delays. These callosal effects are dynamically adapted to the incoming visual activity, so that stimuli providing only weak afferent input are facilitated by callosal pathways, whereas strong visual input via the retinogeniculate pathway tends to be offset by transcallosal inhibition. We also review data highlighting the contribution of callosal input activity to maturation of visual function during early ‘critical periods’ in brain development and describe how interhemispheric transfer of visual information is rerouted in cases of callosal agenesis or following splenial damage. Finally, we provide an overview of alterations in splenium anatomy or function that may be at the basis of visual defects in several pathologic conditions.

Chemokines as new inflammatory players in the pathogenesis of epilepsy.

A large series of clinical and experimental studies supports a link between inflammation and epilepsy, indicating that inflammatory processes within the brain are important contributors to seizure recurrence and precipitation. Systemic inflammation can precipitate seizures in children suffering from epileptic encephalopathies, and hallmarks of a chronic inflammatory state have been found in patients with temporal lobe epilepsy. Research performed on animal models of epilepsy further corroborates the idea that seizures upregulate inflammatory mediators, which in turn may enhance brain excitability and neuronal degeneration. Several inflammatory molecules and their signaling pathways have been implicated in epilepsy. Among these, the chemokine pathway has increasingly gained attention. Chemokines are small cytokines secreted by blood cells, which act as chemoattractants for leukocyte migration. Recent studies indicate that chemokines and their receptors are also produced by brain cells, and are involved in various neurological disorders including epilepsy. In this review, we will focus on a subset of pro-inflammatory chemokines (namely CCL2, CCL3, CCL5, CX3CL1) and their receptors, and their increasingly recognized role in seizure control.

A switch from inter-ocular to inter-hemispheric suppression following monocular deprivation in the rat visual cortex

Binocularity is a key property of primary visual cortex (V1) neurons that is widely used to study synaptic integration in the brain and plastic mechanisms following an altered visual experience. However, it is not clear how the inputs from the two eyes converge onto binocular neurons, and how their interaction is modified by an unbalanced visual drive. Here, using visual evoked potentials recorded in the juvenile rat V1, we report evidence for a suppressive mechanism by which contralateral eye activity inhibits responses from the ipsilateral eye. Accordingly, we found a lack of additivity of the responses evoked independently by the two eyes in the V1, and acute silencing of the contralateral eye resulted in the enhancement of ipsilateral eye responses in cortical neurons. We reverted the relative cortical strength of the two eyes by suturing the contralateral eye shut [monocular deprivation (MD)]. After 7 days of MD, there was a loss of interocular suppression mediated by the contralateral, deprived eye, and weak inputs from the closed eye were functionally inhibited by interhemispheric callosal pathways. We conclude that interocular suppressive mechanisms play a crucial role in shaping normal binocularity in visual cortical neurons, and a switch from interocular to interhemispheric suppression represents a key step in the ocular dominance changes induced by MD. These data have important implications for a deeper understanding of the key mechanisms that underlie activity‐dependent rearrangements of cortical circuits following alteration of sensory experience.