Postnatal Arx transcriptional activity regulates functional properties of PV interneurons

Abstract

Summary: The transcription factor Aristaless-related X-linked gene (Arx) is a monogenic factor in early onset epileptic encephalopathies (EOEEs) and a fundamental regulator of early stages of brain development. However, Arx expression persists in mature GABAergic neurons with an unknown role. To address this issue, we generated a conditional knockout (CKO) mouse in which postnatal Arx was ablated in parvalbumin interneurons (PVIs). Electroencephalogram (EEG) recordings in CKO mice revealed an increase in theta oscillations and the occurrence of occasional seizures. Behavioral analysis uncovered an increase in anxiety. Genome-wide sequencing of fluorescence activated cell sorted (FACS) PVIs revealed that Arx impinged on network excitability via genes primarily associated with synaptic and extracellular matrix pathways. Whole-cell recordings revealed prominent hypoexcitability of various intrinsic and synaptic properties. These results revealed important roles for postnatal Arx expression in PVIs in the control of neural circuits and that dysfunction in those roles alone can cause EOEE-like network abnormalities.

Keywords

• Behavioral Neuroscience
• Molecular Neuroscience
• Cellular Neuroscience
• Transcriptomics