GABAA receptor γ2 subunit mutations linked to human epileptic syndromes differentially affect phasic and tonic inhibition

GABA acts on GABA(A) receptors to evoke both phasic inhibitory synaptic events and persistent, tonic currents. The gamma 2 subunit of the GABAA receptor is involved in both phasic and tonic signaling in the hippocampus. Several mutations of this subunit are linked to human epileptic syndromes with febrile seizures, yet it is not clear how they perturb neuronal activity. Here, we examined the expression and functional impact of recombinant gamma 2 in hippocampal neurons. We show that the K289M mutation has no effect on membrane trafficking and synaptic aggregation of recombinant gamma 2, but accelerates the decay of synaptic currents. In contrast, the R43Q mutation primarily reduces surface expression of recombinant gamma 2. However, it has no dominant effect on synaptic currents but instead reduces tonic GABA currents, at least in part by reducing surface expression of the alpha 5 subunit. Our data suggests that the phenotypic specificity of mutations affecting the GABA(A) receptor gamma 2 gene may result from different actions specific to distinct modes of GABAergic signaling.