Excitatory-Inhibitory Circuit Dysregulation During The Auditory Cortex Critical Period In The Fragile X Syndrome Mouse Model
Fragile X syndrome (FXS), caused by the silencing of the FMR1 gene, is the most common heritable form of intellectual disability and autism. In both FXS and autism, the auditory cortex is of particular interest because of its crucial role in language development, communication, and auditory processing, all of which are hallmark deficits in patients. In the FXS animal model of the Fmr1 knockout (KO) mouse, numerous auditory-related phenotypes have also been described related to abnormal auditory processing and an impaired auditory cortex critical period. While such phenotypes are suggestive of altered excitatory-inhibitory balance in the auditory circuit, few studies have examined synaptic dysregulation in the auditory cortex. Here, we investigate the postnatal maturation of ionotropic glutamate and GABA-mediated synaptic transmission across key developmental ages in auditory forebrain maturation. We first characterized wild-type mice, establishing clear developmental patterns in the naturally developing auditory cortex. We subsequently identified a broad dysregulation of these maturational patterns in the Fmr1 KO mice. Cellular and molecular expression studies of the developmental expression of ionotropic receptor subunits in Chapter 2 revealed altered expression patterns that manifest before ear canal opening, suggestive of dysregulation that manifests before auditory circuits are fully in sync with environmental input. In Chapter 3, we examined the functional maturation of the L4 to L2/3 auditory intracortical circuit, with Fmr1 KO mice revealing aberrant developmental patterns of basal synaptic transmission excitability and synaptic plasticity. In Chapters 4 and 5, we directly investigate the functional maturation of GABAergic and glutamatergic synapses in L2/3 pyramidal neurons in Fmr1 KO mice. Taken together, our results suggest that the loss of FMRP causes an altered regulation and coordination of inhibitory and excitatory synaptic maturation in the auditory cortex, which in part underlie the circuit dysregulation that occurs during its critical period to ultimately elicit auditory-related phenotypes in FXS.