| First Author | Hines RM | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 3130 |
| PubMed ID | 30087324 | Mgi Jnum | J:266404 |
| Mgi Id | MGI:6209234 | Doi | 10.1038/s41467-018-05481-1 |
| Citation | Hines RM, et al. (2018) Developmental seizures and mortality result from reducing GABAA receptor alpha2-subunit interaction with collybistin. Nat Commun 9(1):3130 |
| abstractText | Fast inhibitory synaptic transmission is mediated by gamma-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 alpha2-subunit of GABAARs. To explore the biological relevance of collybistin-alpha2-subunit selectivity, we generate mice with a mutation in the alpha2-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 delta power, which are ameliorated by treatment with the alpha2/alpha3-selective positive modulator, AZD7325. Taken together, our results demonstrate an alpha2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development. |
