Altered ionotropic receptor maturation in the impaired auditory critical periods of Fmr1 knockout mice

University Of Pennsylvania, Philadelphia PA

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Abstract

PROJECT SUMMARY: Fragile X syndrome (FXS), caused by Fmr1 gene silencing, is the most common heritable form of intellectual disability and is often comorbid with autism and seizures. In both FXS and autistic patients, the auditory cortex is of particular interest because of its crucial role in auditory processing, communication, and language development, all of which are hallmark deficits in FXS and autistic patients. Interestingly, Fmr1 knockout mice, the FXS mouse model, have both impaired plasticity during the auditory cortex critical period and altered auditory processing, suggestive of dysregulated auditory circuitry that may contribute to FXS symptoms. The auditory-specific phenotypes in both FXS patients and Fmr1 knockout mice are indicative of excitatory- inhibitory (E-I) imbalance and plasticity deficits. E-I imbalance within neural circuits is thought to underlie aspects of intellectual disability, autism, and epilepsy. E-I regulation is crucial during the critical period of development, a time of experience-dependent plasticity linked to the maturation of neurotransmitter signaling systems. Perturbations during this time can have permanent effects, and several developmental disorders are linked to impaired critical periods. Changes in ionotropic glutamate and GABA receptor expression and function, the primary mediators of excitatory and inhibitory neurotransmission, are pervasive in disorders that cause altered synaptic excitability and plasticity. My data thus far indicate that Fmr1 knockouts have significant changes in GABAA and AMPA receptor subunit expression during key ages in auditory cortex development, both in patterns suggestive of an accelerated maturation of these subunits. Despite the characterized hyperexcitable responses and plasticity deficits within the auditory cortex in FXS, the role of ionotropic receptors in auditory cortex development in FXS is unknown. Therefore, a major premise of this proposal is to evaluate the hypothesis that in the auditory cortex of Fmr1 KOs there is a precocious functional maturation of ionotropic receptors that precedes ear canal opening. My proposed project will integrate histological and electrophysiological approaches to evaluate the development of the auditory cortex in an animal model of intellectual disability, autism, and seizures. Aim 1 will determine whether GABAA receptors in Fmr1 mice have an accelerated functional maturation during the auditory cortex critical period, identifying both regional and synaptic differences across development. Aim 2 will determine whether lack of Fmr1 alters the maturation of NMDAR-only silent synapse to functional AMPAR- and NMDAR-expressing synapses within the auditory thalamocortical connections to identify these receptors' contributions to plasticity. Collectively, the results of my work will determine whether altered developmental functional maturation of ionotropic glutamate and GABA receptors can contribute to E-I imbalance and impaired plasticity within the auditory cortex to elicit the auditory-related phenotypes in FXS.