Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues

Patients with panic disorders show a deficit of GABA(A) receptors in the hippocampus, parahippocampus and orbitofrontal cortex. Synaptic clustering of GABA(A) receptors in mice heterozygous for the gamma 2 subunit was reduced, mainly in hippocampus and cerebral cortex. The gamma 2(+/-) mice showed enhanced behavioral inhibition toward natural aversive stimuli and heightened responsiveness in trace fear conditioning and ambiguous cue discrimination learning. Implicit and spatial memory as well as long-term potentiation in hippocampus were unchanged. Thus gamma 2(+/-) mice represent a model of anxiety characterized by harm avoidance behavior and an explicit memory bias for threat cues, resulting in heightened sensitivity to negative associations. This model implicates GABA(A)-receptor dysfunction in patients as a causal predisposition to anxiety disorders.