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^Δ__E2__^) mice. Truncated ATRX protein was produced from the ATRX^Δ__E2__^ mutant allele with reduced expression level. The ATRX^Δ__E2__^ mice survived and reproduced normally. There was no significant difference in Morris water maze test between wild‐type and ATRX^Δ__E2__^ mice. In a contextual fear conditioning test, however, total freezing time was decreased in ATRX^Δ__E2__^ mice compared to wild‐type mice, suggesting that ATRX^Δ__E2__^ mice have impaired contextual fear memory. ATRX^Δ__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 (αCaMKII) and phosphorylation of glutamate receptor, ionotropic, AMPA 1 (GluR1) were decreased in the hippocampi of the ATRX^Δ__E2__^ mice compared to wild‐type mice. These findings suggest that ATRX^Δ__E2__^ mice may have fear‐associated learning impairment with the dysfunction of αCaMKII and GluR1. The ATRX^Δ__E2__^ mice would be useful tools to investigate the role of the chromatin‐remodeling factor in the pathogenesis of abnormal behaviors and learning impairment. © 2010 Wiley‐Liss, Inc.