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The role of experience in the development of the central visual pathways has been explored in the past through examination of the consequences of imposed periods of continuously abnormal or biased visual input . The massive changes in the visual cortex (area 17) induced by selected early visual experience, especially monocular deprivation (MD) or experience (ME) where patterned visual input is provided to just one eye , are accompanied by profound and long-standing visual deficits . Although the use of exclusively abnormal experience permits identification of those aspects of the visual cortex and of visual function that can be influenced by visual experience during development, this approach may provide a distorted view of the nature of the role of visual experience because of the absence of any normal visual input. In this study a different approach was used whereby animals were provided daily with separate periods of normal (i.e., binocular exposure) and abnormal (monocular exposure) visual experience. We show that 2 hr of daily normal concordant binocular experience (BE) can outweigh or protect against much longer periods of monocular deprivation (MD) and permit the development of normal visual acuities in the two eyes. This result is not what would be expected if all visual input had equal influence on visual development. [Copyright &y& Elsevier]

Our perceptions of the world are based on inputs from our senses, represented as sensory maps in the cortex. The N-methyl-d-aspartate receptor, a glutamatergic ion channel involved in a number of higher-order brain functions, appears to play a variety of roles in the developmental organization of these sensory maps. [Copyright &y& Elsevier]

Neuronal activity is important for both the initial formation and the subsequent refinement of anatomical and physiological features of the mammalian visual system. Here we examine recent evidence concerning the role that spontaneous activity plays in axonal segregation, both of retinogeniculate afferents into eye-specific layers and of geniculocortical afferents into ocular dominance bands. We also assess the role of activity in the generation and plasticity of orientation selectivity in the primary visual cortex. Finally, we review recent challenges to textbook views on how inputs representing the two eyes interact during the critical period of visual cortical plasticity. [Copyright &y& Elsevier]

Summary: It is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that the toxicity of NMDAR-mediated Ca2+ influx is differentially controlled by the cytoplasmic C-terminal domains of GluN2B (CTD2B) and GluN2A (CTD2A). Studying the effects of acute expression of GluN2A/2B-based chimeric subunits with reciprocal exchanges of their CTDs revealed that CTD2B enhances NMDAR toxicity, compared to CTD2A. Furthermore, the vulnerability of forebrain neurons in vitro and in vivo to NMDAR-dependent Ca2+ influx is lowered by replacing the CTD of GluN2B with that of GluN2A by targeted exon exchange in a mouse knockin model. Mechanistically, CTD2B exhibits stronger physical/functional coupling to the PSD-95-nNOS pathway, which suppresses protective CREB activation. Dependence of NMDAR excitotoxicity on the GluN2 CTD subtype can be overcome by inducing high levels of NMDAR activity. Thus, the identity (2A versus 2B) of the GluN2 CTD controls the toxicity dose-response to episodes of NMDAR activity. [ABSTRACT FROM AUTHOR]

Summary Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu 1/5 ) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model ( Fmr1 −/y ) hippocampus, which exhibit exaggerated mGlu 1/5 -induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M 4 ) is excessively translated, and synthesis of M 4 downstream of mGlu 5 activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M 4 activity normalizes core phenotypes in the Fmr1 −/y , including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1 −/y brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain. [ABSTRACT FROM AUTHOR]

Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes. Intriguingly, bursts fired by FXS neurons co-cultured with control astrocytes are indistinguishable from control neurons. Conversely, control neurons exhibit aberrant firing in the presence of FXS astrocytes. Thus, the astrocyte genotype determines the neuronal firing phenotype. Strikingly, astrocytic-conditioned medium, and not the physical presence of astrocytes, is capable of determining the firing phenotype. The mechanistic basis of this effect indicates that the astroglial-derived protein, S100β, restores normal firing by reversing the suppression of a persistent sodium current in FXS neurons., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS. FXS rats exhibit deficient recall of auditory conditioned fear, which is accompanied by a range of in vitro and in vivo deficits in synaptic transmission and plasticity. We find presynaptic mGluR5 in the amygdala, activation of which reverses deficient synaptic transmission and plasticity, thereby restoring normal fear learning in FXS rats. This highlights the importance of modifying the prevailing mGluR-based framework for therapeutic strategies to include circuit-specific differences in FXS pathophysiology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cellular hyperexcitability is a salient feature of fragile X syndrome animal models. The cellular basis of hyperexcitability and how it responds to changing activity states is not fully understood. Here, we show increased axon initial segment length in CA1 of the Fmr1 -/y mouse hippocampus, with increased cellular excitability. This change in length does not result from reduced AIS plasticity, as prolonged depolarization induces changes in AIS length independent of genotype. However, depolarization does reduce cellular excitability, the magnitude of which is greater in Fmr1 -/y neurons. Finally, we observe reduced functional inputs from the entorhinal cortex, with no genotypic difference in the firing rates of CA1 pyramidal neurons. This suggests that AIS-dependent hyperexcitability in Fmr1 -/y mice may result from adaptive or homeostatic regulation induced by reduced functional synaptic connectivity. Thus, while AIS length and intrinsic excitability contribute to cellular hyperexcitability, they may reflect a homeostatic mechanism for reduced synaptic input onto CA1 neurons., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The GluN2 subtype (2A versus 2B) determines biophysical properties and signaling of forebrain NMDA receptors (NMDARs). During development, GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. This "switch" is proposed to be driven by distinct features of GluN2 cytoplasmic C-terminal domains (CTDs), including a unique CaMKII interaction site in GluN2B that drives removal from the synapse. However, these models remain untested in the context of endogenous NMDARs. We show that, although mutating the endogenous GluN2B CaMKII site has secondary effects on GluN2B CTD phosphorylation, the developmental changes in NMDAR composition occur normally and measures of plasticity and synaptogenesis are unaffected. Moreover, the switch proceeds normally in mice that have the GluN2A CTD replaced by that of GluN2B and commences without an observable decline in GluN2B levels but is impaired by GluN2A haploinsufficiency. Thus, GluN2A expression levels, and not GluN2 subtype-specific CTD-driven events, are the overriding factor in the developmental switch in NMDAR composition., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Inhibition provided by local GABAergic interneurons (INs) activates ionotropic GABA A and metabotropic GABA B receptors (GABA B Rs). Despite GABA B Rs representing a major source of inhibition, little is known of their function in distinct IN subtypes. Here, we show that, while the archetypal dendritic-inhibitory somatostatin-expressing INs (SOM-INs) possess high levels of GABA B R on their somato-dendritic surface, they fail to produce significant postsynaptic inhibitory currents. Instead, GABA B Rs selectively inhibit dendritic Ca V 1.2 (L-type) Ca 2+ channels on SOM-IN dendrites, leading to reduced calcium influx and loss of long-term potentiation at excitatory input synapses onto these INs. These data provide a mechanism by which GABA B Rs can contribute to disinhibition and control the efficacy of extrinsic inputs to hippocampal networks., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)