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

Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABA A Rs) 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 GABA A Rs. 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. The inhibitory synaptic protein collybistin (CB) and GABA A R-α subunits are thought to interact, but strength and specificity are unclear. Here the authors study the CB–α2 interaction and show that a mouse mutated in the CB-binding region of α2 displays a loss of specific synapses and seizure.