Impaired fast-spiking, suppressed cortical inhibition, and increased susceptibility to seizures in mice lacking Kv3.2 K+ channel proteins

Voltage-gated K+ channels of the Kv3 subfamily have unusual electrophysiolo gical properties, including activation at very depolarized voltages (positi ve to -10 mV) and very fast deactivation rates, suggesting special roles in neuronal excitability. In the brain, Kv3 channels are prominently expresse d in select neuronal populations, which include fast-spiking (FS) GABAergic interneurons of the neocortex, hippocampus, and caudate, as well as other high-frequency firing neurons. Although evidence points to a key role in hi gh-frequency firing, a definitive understanding of the function of these ch annels has been hampered by a lack of selective pharmacological tools. We t herefore generated mouse lines in which one of the Kv3 genes, Kv3.2, was di srupted by gene-targeting methods. Whole-cell electrophysiological recordin g showed that the ability to fire spikes at high frequencies was impaired i n immunocytochemically identified FS interneurons of deep cortical layers ( 5-6) in which Kv3.2 proteins are normally prominent. No such impairment was found for FS neurons of superficial layers (2-4) in which Kv3.2 proteins a re normally only weakly expressed. These data directly support the hypothes is that Kv3 channels are necessary for high-frequency firing. Moreover, we found that Kv3.2 -/- mice showed specific alterations in their cortical EEG patterns and an increased susceptibility to epileptic seizures consistent with an impairment of cortical inhibitory mechanisms. This implies that, ra ther than producing hyperexcitability of the inhibitory interneurons, Kv3.2 channel elimination suppresses their activity. These data suggest that nor mal cortical operations depend on the ability of inhibitory interneurons to generate high-frequency firing.