Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits.

Kv4.2 channels contribute to the transient, outward K(+) current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit in the learning phase of the Morris water maze (MWM) and significant impairment in the probe trial compared with wild type (WT). Kv4.2 KO mice also demonstrated a specific deficit in contextual learning in the fear-conditioning test, without impairment in the conditioned stimulus or new context condition. Kv4.2 KO mice had normal activity, anxiety levels, and prepulse inhibition compared with WT mice. A compensatory increase in tonic inhibition has been previously described in hippocampal slice recordings from Kv4.2 KO mice. In an attempt to decipher whether increased tonic inhibition contributed to the learning and memory deficits in Kv4.2 KO mice, we administered picrotoxin to block GABA(A) receptors (GABA(A)R), and thereby tonic inhibition. This manipulation had no effect on behavior in the WT or KO mice. Furthermore, total protein levels of the α5 or δ GABA(A)R subunits, which contribute to tonic inhibition, were unchanged in hippocampus. Overall, our findings add to the growing body of evidence, suggesting an important role for Kv4.2 channels in hippocampal-dependent learning and memory.