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Published on: June 17, 2019
Postnatal Arx transcriptional activity regulates functional properties of PV interneurons
Donald J Joseph1, Markus Von Deimling1,2, Yuiko Hasegawa1
1Division of Child Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Rm. 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.
Insights
Postnatal Aristaless-related X-linked gene (Arx) ablation in parvalbumin interneurons caused seizures and anxiety in mice. Arx is crucial for controlling neural circuits and preventing early onset epileptic encephalopathy-like network abnormalities.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Aristaless-related X-linked gene (Arx) is a key factor in early brain development and a cause of early onset epileptic encephalopathies (EOEEs).
- Arx expression continues in mature GABAergic neurons, but its function in these cells is not well understood.
Purpose of the Study:
- To investigate the role of postnatal Arx in parvalbumin interneurons (PVIs) and its contribution to neural circuit function.
- To determine if loss of Arx in PVIs can lead to neurological dysfunction and EOEE-like phenotypes.
Main Methods:
- Generated a conditional knockout (CKO) mouse model with postnatal Arx ablation specifically in PVIs.
- Utilized electroencephalogram (EEG) recordings and behavioral analyses to assess network activity and behavior in CKO mice.
- Performed genome-wide sequencing on fluorescence-activated cell sorted (FACS) PVIs and whole-cell recordings to analyze molecular and electrophysiological changes.
Main Results:
- CKO mice exhibited increased theta oscillations and seizures on EEG recordings.
- Behavioral tests showed increased anxiety in CKO mice.
- Genome-wide sequencing identified synaptic and extracellular matrix pathway genes affected by Arx loss.
- Whole-cell recordings revealed hypoexcitability in intrinsic and synaptic properties of PVIs in CKO mice.
Conclusions:
- Postnatal Arx expression in PVIs plays a critical role in regulating neural circuit function.
- Dysfunction of Arx in PVIs can independently cause EOEE-like network abnormalities.
- These findings highlight a novel role for Arx in mature neuronal function and network stability.
Abstract:
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.
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