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 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(Delta E2)) mice. Truncated ATRX protein was produced from the ATRX(Delta E2) mutant allele with reduced expression level. The ATRX(Delta E2) mice survived and reproduced normally. There was no significant difference in Morris water maze test between wild-type and ATRX(Delta E2) mice. In a contextual fear conditioning test, however, total freezing time was decreased in ATRX(Delta E2) mice compared to wild-type mice, suggesting that ATRX(Delta E2) mice have impaired contextual fear memory. ATRX(Delta E2) 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 (alpha CaMKII) and phosphorylation of glutamate receptor, ionotropic, AMPA 1 (GluR1) were decreased in the hippocampi of the ATRX(Delta E2) mice compared to wild-type mice. These findings suggest that ATRX(Delta E2) mice may have fear-associated learning impairment with the dysfunction of alpha CaMKII and GluR1. The ATRX(Delta E2) mice would be useful tools to investigate the role of the chromatin-remodeling factor in the pathogenesis of abnormal behaviors and learning impairment. (C) 2010 Wiley-Liss, Inc.