Behavioral characterization of mice lacking GIRK/Kir3 channel subunits

G protein-gated inwardly rectifying K(+) (GIRK/Kir3) channels mediate the postsynaptic inhibitory effects of many neurotransmitters and drugs of abuse. The lack of drugs selective for GIRK channels has hindered our ability to study their contributions to behavior. Here, we assessed the impact of GIRK subunit ablation on several behavioral endpoints. Mice were evaluated with respect to open-field motor activity and habituation, anxiety-related behavior, motor co-ordination and ataxia and operant performance. GIRK3 knockout ((-/-)) mice behaved indistinguishably from wild-type mice in this panel of tests. GIRK1(-/-) mice and GIRK2(-/-) mice, however, showed elevated motor activity and delayed habituation to an open field. GIRK2(-/-) mice, and to a lesser extent GIRK1(-/-) mice, also displayed reduced anxiety-related behavior in the elevated plus maze. Both GIRK1(-/-) mice and GIRK2(-/-) mice displayed marked resistance to the ataxic effects of the GABA(B) receptor agonist baclofen in the rotarod test. All GIRK(-/-) mice were able to learn an operant task using food as the reinforcing agent. Within-session progressive ratio scheduling, however, showed elevated lever press behavior in GIRK2(-/-) mice and, to a lesser extent, in GIRK1(-/-) mice. Phenotypic differences between mice lacking GIRK1, GIRK2 and GIRK3 correlate well with the known impact of GIRK subunit ablation on neurotransmitter-gated GIRK currents, arguing that most neuronal GIRK channels contain GIRK1 and/or GIRK2. Altogether, our data suggest that GIRK channels make important contribution to a range of behaviors and may represent points of therapeutic intervention in disorders of anxiety, spasticity and reward.