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

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.