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

摘要

Mutations of the ATRX gene, which encodes an ATP-dependent chromatin-remodeling factor, were identified in patients with alpha-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(DeltaE2)) mice. Truncated ATRX protein was produced from the ATRX(DeltaE2) mutant allele with reduced expression level. The ATRX(DeltaE2) mice survived and reproduced normally. There was no significant difference in Morris water maze test between wild-type and ATRX(DeltaE2) mice. In a contextual fear conditioning test, however, total freezing time was decreased in ATRX(DeltaE2) mice compared to wild-type mice, suggesting that ATRX(DeltaE2) mice have impaired contextual fear memory. ATRX(DeltaE2) 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 (alphaCaMKII) and phosphorylation of glutamate receptor, ionotropic, AMPA 1 (GluR1) were decreased in the hippocampi of the ATRX(DeltaE2) mice compared to wild-type mice. These findings suggest that ATRX(DeltaE2) mice may have fear-associated learning impairment with the dysfunction of alphaCaMKII and GluR1. The ATRX(DeltaE2) mice would be useful tools to investigate the role of the chromatin-remodeling factor in the pathogenesis of abnormal behaviors and learning impairment.