Hippocampus-related cognitive disorders develop in the absence of epilepsy and ataxia in the heterozygous mutant mice .

-associated epilepsy and ataxia frequently accompany cognitive impairments as devastating co-morbidities. However, it is unclear whether the cognitive deficits are consequences secondary to the neurological symptoms elicited by mutations. To address this issue, mutant mice (), and in particular /+ heterozygotes, serve as a suitable model system, given that /+ heterozygotes fail to display spontaneous absence epilepsy and ataxia typically observed in / homozygotes. Here, we examined hippocampus-dependent behaviors and hippocampal learning-related synaptic plasticity in mice. In behavioral analyses of /+ and /, acquisition and retention of spatial reference memory were characteristically impaired in the Morris water maze task, while working memory was intact in the eight-arm radial maze and T-maze tasks. /+ heterozygotes showed normal motor function in contrast to / homozygotes. In electrophysiological analyses, Schaffer collateral-CA1 synapses showed a deficit in the maintenance of long-term potentiation in /+ and / mice and an increased paired-pulse facilitation induced by paired pulses with 100 ms in / mice. Our results indicate that the mutation causes a dominant disorder of the hippocampus-related memory and synaptic plasticity, raising the possibility that in -associated human diseases, functionally aberrant Ca2.1 Ca channels actively induce the observed cognitive deficits independently of the neurological symptoms.