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Developmental seizures and mortality result from reducing GABAA receptor ?2-subunit interaction with collybistin.

ABSTRACT: Fast inhibitory synaptic transmission is mediated by ?-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 ?2-subunit of GABAARs. To explore the biological relevance of collybistin-?2-subunit selectivity, we generate mice with a mutation in the ?2-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 ? power, which are ameliorated by treatment with the ?2/?3-selective positive modulator, AZD7325. Taken together, our results demonstrate an ?2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development.

SUBMITTER: Hines RM

PROVIDER: S-EPMC6081406 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Hines Rochelle M RM Maric Hans Michael HM Hines Dustin J DJ Modgil Amit A Panzanelli Patrizia P Nakamura Yasuko Y Nathanson Anna J AJ Cross Alan A Deeb Tarek T Brandon Nicholas J NJ Davies Paul P Fritschy Jean-Marc JM Schindelin Hermann H Moss Stephen J SJ

Nature communications 20180807 1

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-coll ...[more]

PMID: 30087324

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Developmental seizures and mortality result from reducing GABAA receptor ?2-subunit interaction with collybistin.

Publications

Developmental seizures and mortality result from reducing GABA<sub>A</sub> receptor α2-subunit interaction with collybistin.

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