Developmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin

Rochelle M. Hines (), Hans Michael Maric, Dustin J. Hines, Amit Modgil, Patrizia Panzanelli, Yasuko Nakamura, Anna J. Nathanson, Alan Cross, Tarek Deeb, Nicholas J. Brandon, Paul Davies, Jean-Marc Fritschy, Hermann Schindelin and Stephen J. Moss ()
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Rochelle M. Hines: Tufts University School of Medicine
Hans Michael Maric: University of Würzburg
Dustin J. Hines: Tufts University School of Medicine
Amit Modgil: Tufts University School of Medicine
Patrizia Panzanelli: University of Turin
Yasuko Nakamura: Tufts University School of Medicine
Anna J. Nathanson: Tufts University School of Medicine
Alan Cross: AstraZeneca Neuroscience iMED, Biotech Unit
Tarek Deeb: Tufts University School of Medicine
Nicholas J. Brandon: AstraZeneca Neuroscience iMED, Biotech Unit
Paul Davies: Tufts University School of Medicine
Jean-Marc Fritschy: University of Zurich
Hermann Schindelin: University of Würzburg
Stephen J. Moss: Tufts University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents. Gabra2–1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development.

Date: 2018
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DOI: 10.1038/s41467-018-05481-1

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