title: Reduced expression of the ATRX gene, a chromatin-remodeling factor, causes hippocampal dysfunction in mice.
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.
authors.affiliation: Department of Clinical Laboratory and Molecular Pathology, University of Toyama, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nogami
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Beppu
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokoro
authors.forename: Shigeki
authors.initials: S
authors.lastname: Moriguchi
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishii
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimada
authors.forename: Hisao
authors.initials: H
authors.lastname: Nishijo
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.forename: Isao
authors.initials: I
authors.lastname: Kitajima
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000503:physiopathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003214:Conditioning, Classical / Q000502:physiology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D005239:Fear / Q000502:physiology* / Q000523:psychology; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D006801:Humans; D007859:Learning Disabilities / Q000235:genetics; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D038901:X-Linked Intellectual Disability / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism*; D000075924:X-linked Nuclear Protein; D017085:alpha-Thalassemia / Q000235:genetics / Q000378:metabolism
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004265:DNA Helicases; D009687:Nuclear Proteins; D018091:Receptors, AMPA; D000075924:X-linked Nuclear Protein; C490462:Atrx protein, mouse