TY  - JOUR
A1  - Hines, Rochelle M.
A1  - Maric, Hans Michael
A1  - Hines, Dustin J.
A1  - Modgil, Amit
A1  - Panzanelli, Patrizia
A1  - Nakamura, Yasuko
A1  - Nathanson, Anna J.
A1  - Cross, Alan
A1  - Deeb, Tarek
A1  - Brandon, Nicholas J.
A1  - Davies, Paul
A1  - Fritschy, Jean-Marc
A1  - Schindelin, Hermann
A1  - Moss, Stephen J.
T1  - Developmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin
JF  - Nature Communications
N2  - 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.
KW  - cellular neuroscience
KW  - ion channels in the nervous system
KW  - neurotransmitters
KW  - synaptic development
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320719
VL  - 9
ER  -