Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability

Author(s): Speca, DJ; Ogata, G; Mandikian, D; Bishop, HI; Wiler, SW; Eum, K; Wenzel, HJ; Doisy, ET; Matt, L; Campi, KL; Golub, MS; Nerbonne, JM; Hell, JW; Trainor, BC; Sack, JT; Schwartzkroin, PA; Trimmer, JS | Abstract: The Kv2.1 delayed rectifier potassium channel exhibits high-level expression in both principal and inhibitory neurons throughout the central nervous system, including prominent expression in hippocampal neurons. Studies of in vitro preparations suggest that Kv2.1 is a key yet conditional regulator of intrinsic neuronal excitability, mediated by changes in Kv2.1 expression, localization and function via activity-dependent regulation of Kv2.1 phosphorylation. Here we identify neurological and behavioral deficits in mutant (Kv2.1-/-) mice lacking this channel. Kv2.1-/-mice have grossly normal characteristics. No impairment in vision or motor coordination was apparent, although Kv2.1-/-mice exhibit reduced body weight. The anatomic structure and expression of related Kv channels in the brains of Kv2.1-/-mice appear unchanged. Delayed rectifier potassium current is diminished in hippocampal neurons cultured from Kv2.1-/-animals. Field recordings from hippocampal slices of Kv2.1-/-mice reveal hyperexcitability in response to the convulsant bicuculline, and epileptiform activity in response to stimulation. In Kv2.1-/-mice, long-term potentiation at the Schaffer collateral - CA1 synapse is decreased. Kv2.1-/-mice are strikingly hyperactive, and exhibit defects in spatial learning, failing to improve performance in a Morris Water Maze task. Kv2.1-/-mice are hypersensitive to the effects of the convulsants flurothyl and pilocarpine, consistent with a role for Kv2.1 as a conditional suppressor of neuronal activity. Although not prone to spontaneous seizures, Kv2.1-/-mice exhibit accelerated seizure progression. Together, these findings suggest homeostatic suppression of elevated neuronal activity by Kv2.1 plays a central role in regulating neuronal network function. Kv2.1 mutant mice are strikingly hyperactive, susceptible to convulsant-induced seizures and defective in learning. © 2014 John Wiley a Sons Ltd and International Behavioural and Neural Genetics Society.