Postnatal Arx transcriptional activity regulates functional properties of PV interneurons
Donald J. Joseph,
Markus Von Deimling,
Yuiko Hasegawa,
Ana G. Cristancho,
Rebecca C. Ahrens-Nicklas,
Stephanie L. Rogers,
Rashmi Risbud,
Almedia J. McCoy,
Eric D. Marsh
Affiliations
Donald J. Joseph
Division of Child Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Rm. 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
Markus Von Deimling
Division of Child Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Rm. 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA; Klinik für Urologie, Städtisches Klinikum Lüneburg, Bögelstraße 1, 21339 Lüneburg, Germany
Yuiko Hasegawa
Division of Child Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Rm. 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
Ana G. Cristancho
Division of Child Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Rm. 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
Rebecca C. Ahrens-Nicklas
Division of Metabolism, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Stephanie L. Rogers
Division of Child Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Rm. 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
Rashmi Risbud
Division of Child Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Rm. 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
Almedia J. McCoy
Division of Child Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Rm. 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
Eric D. Marsh
Division of Child Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Rm. 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
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.
