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 γ2 subunit was reduced, mainly in hippocampus and cerebral cortex. The γ2(+/-) 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 γ2(+/-) 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.
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