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- Title
Dysregulation of GABAA Receptor-Mediated Neurotransmission during the Auditory Cortex Critical Period in the Fragile X Syndrome Mouse Model.
- Authors
Song, Yeri J; Xing, Bo; Barbour, Aaron J; Zhou, Chengwen; Jensen, Frances E
- Abstract
Fragile X syndrome (FXS) is the leading monogenic form of intellectual disability and autism, with patients exhibiting numerous auditory-related phenotypes during their developmental period, including communication, language development, and auditory processing deficits. Despite FXS studies describing excitatory–inhibitory (E–I) imbalance in the auditory circuit and an impaired auditory critical period, evaluation of E–I circuitry maturation in the auditory cortex of FXS models remains limited. Here, we examined GABAA receptor (GABAAR)-mediated inhibitory synaptic transmission within the auditory cortex, characterizing normal intracortical circuit development patterns in wild-type (WT) mice and examining their dysregulation in developing Fmr1 knock-out (KO) mice. Electrophysiological recordings revealed gradual developmental shifts in WT L4-L2/3 connectivity, where circuit excitability significantly increased after critical period onset. KO mice exhibited accelerated developmental shifts related to aberrant GABAergic signaling. Specifically, Fmr1 KO L2/3 pyramidal neurons have enhanced developmental sensitivity to pharmacological GABAAR modulators, altered maturation of GABAAR voltage-dependent conductance, with additional presynaptic GABA release alterations. These differences are further accompanied by alterations in developmental long-term potentiation. Together, our results suggest that altered GABAergic signaling within developing Fmr1 KOs impairs the normal patterning of E–I circuit and synaptic plasticity maturation to contribute to the impaired auditory cortex critical period and functional auditory deficits in FXS.
- Publication
Cerebral Cortex, 2022, Vol 32, Issue 1, p197
- ISSN
1047-3211
- Publication type
Article
- DOI
10.1093/cercor/bhab203