title: Neural activity changes underlying the working memory deficit in alpha-CaMKII heterozygous knockout mice.
abstract: The alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) is expressed abundantly in the forebrain and is considered to have an essential role in synaptic plasticity and cognitive function. Previously, we reported that mice heterozygous for a null mutation of alpha-CaMKII (alpha-CaMKII+/-) have profoundly dysregulated behaviors including a severe working memory deficit, which is an endophenotype of schizophrenia and other psychiatric disorders. In addition, we found that almost all the neurons in the dentate gyrus (DG) of the mutant mice failed to mature at molecular, morphological and electrophysiological levels. In the present study, to identify the brain substrates of the working memory deficit in the mutant mice, we examined the expression of the immediate early genes (IEGs), c-Fos and Arc, in the brain after a working memory version of the eight-arm radial maze test. c-Fos expression was abolished almost completely in the DG and was reduced significantly in neurons in the CA1 and CA3 areas of the hippocampus, central amygdala, and medial prefrontal cortex (mPFC). However, c-Fos expression was intact in the entorhinal and visual cortices. Immunohistochemical studies using arc promoter driven dVenus transgenic mice demonstrated that arc gene activation after the working memory task occurred in mature, but not immature neurons in the DG of wild-type mice. These results suggest crucial insights for the neural circuits underlying spatial mnemonic processing during a working memory task and suggest the involvement of alpha-CaMKII in the proper maturation and integration of DG neurons into these circuits.
authors.affiliation: Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University Toyoake, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsuo
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamasaki
authors.forename: Koji
authors.initials: K
authors.lastname: Ohira
authors.forename: Keizo
authors.initials: K
authors.lastname: Takao
authors.forename: Keiko
authors.initials: K
authors.lastname: Toyama
authors.forename: Megumi
authors.initials: M
authors.lastname: Eguchi
authors.forename: Shun
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa