Reduced expression of the ATRX gene, a chromatin-remodeling factor, causes hippocampal dysfunction in mice

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

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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 (ATRX ΔE2) mice. Truncated ATRX protein was produced from the ATRX ΔE2 mutant allele with reduced expression level. The ATRX ΔE2 mice survived and reproduced normally. There was no significant difference in Morris water maze test between wild-type and ATRX ΔE2 mice. In a contextual fear conditioning test, however, total freezing time was decreased in ATRX ΔE2 mice compared to wild-type mice, suggesting that ATRX ΔE2 mice have impaired contextual fear memory. ATRX ΔE2 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 ATRX ΔE2 mice compared to wild-type mice. These findings suggest that ATRX ΔE2 mice may have fear-associated learning impairment with the dysfunction of αCaMKII and GluR1. The ATRX ΔE2 mice would be useful tools to investigate the role of the chromatin-remodeling factor in the pathogenesis of abnormal behaviors and learning impairment.

Original languageEnglish
Pages (from-to)678-687
Number of pages10
JournalHippocampus
Volume21
Issue number6
DOIs
Publication statusPublished - 2011 Jun

Keywords

  • ATRX
  • CaMKII
  • GluR1
  • Learning
  • Phosphorylation

ASJC Scopus subject areas

  • Cognitive Neuroscience

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