Postnatal <i>Arx</i> Transcriptional Activity Regulates Functional Network Properties of PV Interneurons

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, but its role in the mature brain is unknown. To address this issue, we generated a conditional knockout (CKO) mouse in which postnatal Arx expression was selectively ablated in parvalbumin interneurons (PVIs). Electroencephalogram (EEG) recordings in CKO mice revealed an increase in hippocampal theta oscillations and the occurrence of occasional seizures. Behavioral analysis uncovered an increase in anxiety in these mice. Genome-wide sequencing of fluorescence activated cell sorted (FACS) PVIs from hippocampal and cortical brain regions revealed that Arx impinged on network excitability via a vast array of genes that are predominantly associated with synaptic and extracellular matrix pathways. Whole-cell recordings from CKO mice revealed prominent hypo-excitability of various PVI intrinsic and excitatory synaptic properties. These results revealed important functional 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. Thus, restoration of postnatal Arx signaling in PVIs following onset of Arx-linked EOEEs represents a novel and more efficacious therapeutic approach for treatment of these pharmacoresistant epileptic disorders.