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Cellular and circuit mechanisms of neocortical dysfunction in Fragile X Syndrome

Abstract : This study explores the evoked responses, intrinsic and spontaneous activity of two different neuronal populations in the hind paw region of the primary somatosensory cortex (S1) of mice. Initially, we explored information processing in these neurons under normal physiological conditions, and subsequently in a mouse model of Fragile X Syndrome (FXS). FXS is the most common form of inherited mental retardation syndrome and a frequent cause of autism spectrum disorders (ASD). FXS is a single gene (Fmr1) disorder, which can be reliably modeled by a mutant mouse model, the Fmr1 knockout (Fmr1-/y) mouse. Hyperexcitability of neocortical networks and hypersensibility to sensory stimuli are prominent features of FXS and ASD. We previously established a strong causal link between a channelopathy, hyperexcitability of neurons in the primary sensory region of the neocortex and sensory hypersensitivity in this mouse model. In the current study, we extended these findings, by conducting a detailed exploration of the processing of tactile sensory information (evoked by hind paw stimulation) in the neocortex of these mice.Most of our knowledge regarding information processing in S1 comes from studies of the whisker-related barrel cortex (which processes tactile-related sensory information derived from the whiskers), yet the processing of sensory inputs from the hind-paws is poorly understood. Using in vivo whole-cell patch-clamp recordings, we classified the cells into suprathreshold responders (the cells which responded to the hind-paw stimulations with an action potential), subthreshold responders (the cells responded without eliciting an action potential) and non-responder cells (neurons which did not show any response). We then compared the evoked sub- and supra-threshold responses, intrinsic properties, and spontaneous activity of layer (L) 2/3 pyramidal neurons of the S1 hind-paw (S1-HP) region of anaesthetized wild type (WT) and Fmr1-/y mice. We identified spontaneous, intrinsic and evoked response alterations in Fmr1-/y mice. We probed possible mechanisms contributing to this sensory impairment in Fmr1-/y mice. Finally, we tested the possibility of correcting pathophysiological alterations in these neurons using specific pharmacological agents targeting the ion channel defects described previously by our team.
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Arjun Azhikkattuparambil Bhaskaran. Cellular and circuit mechanisms of neocortical dysfunction in Fragile X Syndrome. Neurons and Cognition [q-bio.NC]. Université de Bordeaux, 2018. English. ⟨NNT : 2018BORD0244⟩. ⟨tel-02426234⟩

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