UC Riverside

Autism spectrum disorder (ASD) is often associated with challenges in social communication and language delays, and it is characterized by sensory deficits such as hypo- or hypersensitivity. Auditory sensory hypersensitivity is a well-established phenotype of FXS, a leading genetic cause of ASD. Electroencephalogram (EEG) recordings show similar phenotypes in humans with FXS and in Fmr1 knockout (KO) mouse models, namely increased baseline gamma power, impaired habituation of the event-related potential (ERP) in response to noise bursts, and reduced phase-locking to amplitude-modulated noise. These disruptions to auditory signals and sound processing may be a result of altered excitation and inhibition levels in the brain, and they may be differentially affected by cortical and subcortical auditory regions. Inhibitory and excitatory signals are associated with GABAergic neurons and glutamatergic signaling, respectively. In the present studies, we seek to identify the contribution of inhibitory neurons, namely parvalbumin-positive (PV) neurons, to sound processing in the AC, to test whether targeting upregulated metabotropic glutamate activity (mGluR5) in FXS alleviates symptoms, and to further elucidate the role of subcortical auditory structures in regulating phase-locking to temporally modulated auditory signals. We found that PV neurons in the AC regulate resting gamma power and the 40-Hz click ASSR, while FMRP in the midbrain regulate temporal processing of gaps presented repeatedly in noise stimuli, presenting a double-dissociative role of the auditory cortex and midbrain. Furthermore, targeting mGluR5 in FXS showed benefits in resting gamma power when coupled with minocycline. These findings further our understanding of excitation and inhibition in auditory functioning in FXS and the differential contributions of cortical and subcortical regions.