Testing the Excitability of Inhibitory Neurons

Huntsman, Molly-Maureen; Corbin, Joshua

Abstract

Neurological disorders such as epilepsy and Fragile X Syndrome (FXS) are characterized with imbalances in excitatory and inhibitory neurotransmission. Patients with FXS exhibit a hyperexcitable phenotype evidenced by severe cognitive deficits, increased incidence of recurring seizures, social anxiety and hypersensitivity to sensory stimuli. We hypothesize that defects in inhibitory neurotransmission in primary somatosensory cortex underlie aspects of the hyperexcitable phenotype of FXS, including its comorbidity with epilepsy. In this project, we use a multidisciplinary approach combining electrophysiological and anatomical analyses with mouse genetic rescues to study the Fragile X phenotype in a cortical area relevant for both cognitive and sensory dysfunction. Our primary goals are to determine the mechanism of synaptic and network dysfunction in FXS. We will examine inhibitory neuron dysfunction through the view of two complementary theories that are hypothesized to lead to the hyperexcitable phenotype observed in FXS. We will additionally test whether altered excitability in inhibitory circuits can be rescued genetically in FXS mutant mice.

Public Health Relevance

Fragile X Syndrome (FXS) is a debilitating disorder marked by severe cognitive impairments and comorbidities with other disorders such as autism and childhood epilepsy. Experiments in this proposal are designed to unravel the mechanism of synapse dysfunction and to rescue these defects in cortical microcircuits in a mouse model of FXS. This knowledge will therefore contribute to a basic understanding in the development of the pathophysiological process associated with developmental disorders.