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

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 appears 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.

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

“…Specifically, B6.Q54 mice express a higher level of Kcnv2, a silent K + channel subunit that forms heterotetramers with K V 2.1 and suppresses delayed rectifier current. Reduced K V 2.1-mediated current is predicted to enhance excitability of neurons from B6.Q54 mice, similar to what has been demonstrated for K V 2.1 knockout mice, and evoked action potential broadening during a train of action potentials (26), which is what we observed in this study (Fig. 2).…”

Amigo Adhesion Protein Regulates Development of Neural Circuits in Zebrafish Brain

“…During the preparation of this manuscript, a study on Kv2.1 knock-out mice appeared showing that deficiency of the Kv2.1 channel leads to neuronal and behavioral hyperexcitability (50). General locomotor activity in the Kv2.1 knock-out mice was found to be strongly enhanced, clearly resembling the enhanced activity in the amigo1 morphants that we had found in the current study.…”

Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells

“…In combination with patch-clamp electrophysiology, GxTX pharmacology is currently the most stringent test of whether Kv2 channels contribute to electrical signaling (13). In neurons and pancreatic islet cells, GxTX inhibits delayed rectifier current with minimal effects on other current types and has been recently used to reveal unexpected contributions of Kv2 channels to electrical signaling (13,31,32). Based on the effects of GxTX on Kv2 channel gating and the behavior of radiolabeled GxTX (30), we suspected GxTX might bind much more weakly when the channels become activated by voltage.…”

“…The channel's activity shapes the repetitive firing properties of neurons (13), and Kv2.1 is homeostatically regulated in response to electrical activity (55). The up-regulation of Kv2.1 activity is proposed to relieve excitotoxic stress by suppressing neuronal hyperexcitability and seizure activity (32). However, under pathological conditions such as ischemia from stroke, up-regulation of Kv2.1 activity leads to apoptosis (56).…”