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MANUSCRIPT ID

• Title

Neural activity changes underlying the working memory deficit in alpha-camKii heterozygous mice

• Reference

Matsuo N, Yamasaki N, Ohira K, Takao K, Toyama K, Eguchi M, Yamaguchi S, Miyakawa T. Neural activity changes underlying the working memory deficit in alpha-CaMKII heterozygous knockout mice. Front Behav Neurosci. 2009;3:20. Epub 2009 Sep 2.

• 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.

• Keywords

alpha-CaMKII, working memory, dentate gyrus, schizophrenia, immediate-early genes, c-fos

• Input Author

ACF

MANUSCRIPT DETAILS

• Introduction/Aims

α-CaMKII a protein kinase critical for LTP, learning, and memory: knock-out mice show deficits in both domains

Heterozygous K.O. mice have other phenotypes

    Behavioral : working memory deficits (proposed endophenotype of psychiatric disorders in humans), increased locomotor activity, decreased anxiety-like behavior, decreased depression-like behavior, periodic mood-change-like behavior
    Physiologic phenotypes: increased dopamine turnover in striatum and increased D1-like receptor binding in the dentate gyrus (DG)
    Cellular phenotypes: immature DG neurons (assayed by molecular profile, morphology, and electrophysiology

Immediate early genes (IEGs) are transcription factors whose expression has been used as a marker for neuronal activity as they are rapidly and transiently expressed following neuronal stimuli (examples are c-Fos and Arc)

Use IEG expression patterns following a working memory task to determine which brain regions are dysfunctional in α-CaMKII+/-