title: Age-dependent kainate sensitivity in heterozygous rolling Nagoya Cav2.1 channel mutant mice.
abstract: Cav2.1α1 is involved in glutamate release. The kainate-induced intensive firing of neurons via glutamate receptors causes seizure and neuronal damage, especially in the hippocampus. Cav2.1α1 mutation in homozygous rolling Nagoya (rol/rol) mice caused reduced Ca(2+) permeability compared to wild-type mice. The rol/rol mice exhibited ataxia approximately after 2 weeks of age. Although we have reported that heterozygous rolling Nagoya (rol/+) mice show age-dependent behavioral changes, sensitivity to kainate has not been examined. To examine the relationship between Cav2.1 function and neurological disease, we investigated how Cav2.1 is related to kainate-induced seizure and neuronal damage using 2- and 18-month-old rol/+ mice. The seizure scores of 18-month-old rol/+ mice that received 20mg/kg kainate intraperitoneally were significantly lower than those of wild-type mice. As a consequence of seizure, kainate induced delayed neuronal damage along with astrocytic growth in the hippocampus in wild-type mice, with a moderate effect observed in rol/+ mice. In the hippocampus of 18-month-old rol/+ mice, the levels of mutant-type Cav2.1α1 were increased compared to +/+ mice. The phosphorylation of p38, a mitogen-activated protein kinase (MAPK) activated by kainate, was not increased after kainate injection compared to +/+ mice. No difference was observed between 2-month-old rol/+ and wild-type mice intraperitoneally injected with 20mg/kg kainate in these analyses. These findings suggest that rol/+ mice experience age-related changes in sensitivity to kainate due to changes in the p38 MAPK signaling pathway via a mutant Cav2.1 channel. Hence, rol/+ mice may represent a novel model to delineate the association between Cav2.1 function, synaptic transmission, and the postsynaptic signaling cascade.
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Tae Yeon
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Yoshimoto
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Aoyama
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Niimi
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: etakahashi@brain.riken.jp.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Chitoshi
authors.initials: C
authors.lastname: Itakura
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D060888:Real-Time Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020864:Calcium Channels, N-Type; D007608:Kainic Acid; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Cav2.1α(1) mutation; Hippocampus; Kainate; Neuronal damage; Rolling Nagoya mouse; Seizure