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


Hines, Rochelle M; Maric, Hans Michael; Hines, Dustin J; Modgil, Amit; Panzanelli, Patrizia; Nakamura, Yasuko; Nathanson, Anna J; Cross, Alan; Deeb, Tarek; Brandon, Nicholas J; Davies, Paul; Fritschy, Jean-Marc; Schindelin, Hermann; Moss, Stephen J (2018). Developmental seizures and mortality result from reducing GABA receptor α2-subunit interaction with collybistin. Nature Communications, 9(1):3130.

Abstract

Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABARs) 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 GABARs. 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.

Abstract

Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABARs) 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 GABARs. 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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:7 August 2018
Deposited On:05 Mar 2019 15:25
Last Modified:25 Sep 2019 00:08
Publisher:Nature Publishing Group
ISSN:2041-1723
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41467-018-05481-1
PubMed ID:30087324

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