Reduced expression of the ATRX gene,a chromatin‐remodeling factor,causes hippocampal dysfunction in mice |
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| Authors: | Tatsuya Nogami Hideyuki Beppu Takashi Tokoro Shigeki Moriguchi Norifumi Shioda Kohji Fukunaga Toshihisa Ohtsuka Yoko Ishii Masakiyo Sasahara Yutaka Shimada Hisao Nishijo En Li Isao Kitajima |
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| Affiliation: | 1. Department of Clinical Laboratory and Molecular Pathology, University of Toyama, Toyama 930‐0194, Japan;2. Department of Japanese Oriental Medicine, University of Toyama, Toyama 930‐0194, Japan;3. Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts;4. Department of Pharmacology, Tohoku University, Sendai 980‐8578, Japan;5. Department of Biochemistry, University of Yamanashi, Chuo, 409‐3898, Japan;6. Department of Pathology, University of Toyama, Toyama 930‐0194, Japan;7. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332‐0012, Japan;8. System Emotional Science, University of Toyama, Toyama 930‐0194, Japan;9. Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts |
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| Abstract: | Mutations of the ATRX gene, which encodes an ATP‐dependent chromatin‐remodeling factor, were identified in patients with α‐thalassemia X‐linked mental retardation (ATR‐X) syndrome. There is a milder variant of ATR‐X syndrome caused by mutations in the Exon 2 of the gene. To examine the impact of the Exon 2 mutation on neuronal development, we generated ATRX mutant (ATRXΔE2) mice. Truncated ATRX protein was produced from the ATRXΔE2 mutant allele with reduced expression level. The ATRXΔE2 mice survived and reproduced normally. There was no significant difference in Morris water maze test between wild‐type and ATRXΔE2 mice. In a contextual fear conditioning test, however, total freezing time was decreased in ATRXΔE2 mice compared to wild‐type mice, suggesting that ATRXΔE2 mice have impaired contextual fear memory. ATRXΔE2 mice showed significantly reduced long‐term potentiation in the hippocampal CA1 region evoked by high‐frequency stimulation. Moreover, autophosphorylation of calcium‐calmodulin‐dependent kinase II (αCaMKII) and phosphorylation of glutamate receptor, ionotropic, AMPA 1 (GluR1) were decreased in the hippocampi of the ATRXΔE2 mice compared to wild‐type mice. These findings suggest that ATRXΔE2 mice may have fear‐associated learning impairment with the dysfunction of αCaMKII and GluR1. The ATRXΔE2 mice would be useful tools to investigate the role of the chromatin‐remodeling factor in the pathogenesis of abnormal behaviors and learning impairment. © 2010 Wiley‐Liss, Inc. |
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| Keywords: | ATRX CaMKII GluR1 learning phosphorylation |
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