Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability.
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.
Department of Neurobiology, Physiology and Behavior, College of Biological Sciences.
D J
DJ
Speca
G
G
Ogata
D
D
Mandikian
H I
HI
Bishop
S W
SW
Wiler
K
K
Eum
H Jürgen
HJ
Wenzel
E T
ET
Doisy
L
L
Matt
K L
KL
Campi
M S
MS
Golub
J M
JM
Nerbonne
J W
JW
Hell
B C
BC
Trainor
J T
JT
Sack
P A
PA
Schwartzkroin
J S
JS
Trimmer
D000200:Action Potentials; D000818:Animals; D003292:Convulsants / Q000494:pharmacology; D005481:Flurothyl / Q000494:pharmacology; D017353:Gene Deletion; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D010862:Pilocarpine / Q000494:pharmacology; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology; D051669:Shab Potassium Channels / Q000235:genetics / Q000378:metabolism*
D003292:Convulsants; C496990:Kcnb1 protein, mouse; D051669:Shab Potassium Channels; D010862:Pilocarpine; D005481:Flurothyl
Hyperactivity; Kcnb1; Kcnb1tm1Dgen; long-term potentiation; seizure