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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 GABA A  receptor (GABA A R)-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 GABA A R modulators, altered maturation of GABA A R 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.

Dysregulation of GABA A Receptor-Mediated Neurotransmission during the Auditory Cortex Critical Period in the Fragile X Syndrome Mouse Model