Document Type
Article
Publication Date
8-7-2018
Publication Title
Nature Communications
Volume
9
First page number:
1
Last page number:
15
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.
Disciplines
Biological Psychology
File Format
File Size
3.354 Kb
Language
English
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Repository Citation
Hines, R. M.,
Maric, H. M.,
Hines, D. J.,
Modgil, A.,
Panzanelli, P.,
Nakamura, Y.,
Nathanson, A. J.,
Cross, A.,
Deeb, T.,
Brandon, N. J.,
Davies, P.,
Fritschy, J.,
Schindelin, H.,
Moss, S. J.
(2018).
Developmental Seizures and Mortality Result from Reducing GABAA Receptor α2-subunit Interaction with Collybistin.
Nature Communications, 9
1-15.
http://dx.doi.org/10.1038/s41467-018-05481-1