Disruption of the ether-a-go-go K+ channel gene BEC1/KCNH3 enhances cognitive function.
The K+ channel, one of the determinants for neuronal excitability, is genetically heterogeneous, and various K+ channel genes are expressed in the CNS. The therapeutic potential of K+ channel blockers for cognitive enhancement has been discussed, but the contribution each K+ channel gene makes to cognitive function remains obscure. BEC1 (KCNH3) is a member of the K+ channel superfamily that shows forebrain-preferential distribution. Here, we show the critical involvement of BEC1 in cognitive function. BEC1 knock-out mice performed behavioral tasks related to working memory, reference memory, and attention better than their wild-type littermates. Enhanced performance was also observed in heterozygous mutants. The knock-out mice had neither the seizures nor the motor dysfunction that are often observed in K+ channel-deficient mice. In contrast to when it is disrupted, overexpression of BEC1 in the forebrain caused the impaired performance of those tasks. It was also found that altering BEC1 expression could change hippocampal neuronal excitability and synaptic plasticity. The results indicate that BEC1 may represent the first K+ channel that contributes preferentially and bidirectionally to cognitive function.
Miyake
Akira
A
Drug Discovery Research, Astellas Pharma Inc., Ibaraki 305-8585, Japan. akira.miyake@jp.astellas.com
Takahashi
Shinji
S
Nakamura
Yukihiro
Y
Inamura
Kohei
K
Matsumoto
Shun-Ichiro
S
Mochizuki
Shinobu
S
Katou
Masao
M
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000071186:Beclin-1; D003071:Cognition / Q000502:physiology*; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D051638:Ether-A-Go-Go Potassium Channels; C496887:Kcnh3 protein, mouse