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We generated<jats:italic>ATRX<\/jats:italic>mutant mice lacking exon 2 (<jats:italic>ATRX<\/jats:italic><jats:sup>\u0394<jats:italic>E2<\/jats:italic><\/jats:sup>mice), a mutation that mimics exon 2 mutations seen in human patients and associated with milder forms of retardation.<jats:italic>ATRX<\/jats:italic><jats:sup>\u0394<jats:italic>E2<\/jats:italic><\/jats:sup>mice exhibited abnormal dendritic spine formation in the medial prefrontal cortex (mPFC). Consistent with other mouse models of mental retardation,<jats:italic>ATRX<\/jats:italic><jats:sup>\u0394<jats:italic>E2<\/jats:italic><\/jats:sup>mice exhibited longer and thinner dendritic spines compared with wild-type mice without changes in spine number. Interestingly, aberrant increased calcium\/calmodulin-dependent protein kinase II (CaMKII) activity was observed in the mPFC of<jats:italic>ATRX<\/jats:italic><jats:sup>\u0394<jats:italic>E2<\/jats:italic><\/jats:sup>mice. Increased CaMKII autophosphorylation and activity were associated with increased phosphorylation of the Rac1-guanine nucleotide exchange factors (GEFs) T-cell lymphoma invasion and metastasis 1 (Tiam1) and kalirin-7, known substrates of CaMKII. We confirmed increased phosphorylation of p21-activated kinases (PAKs) in mPFC extracts. Furthermore, reduced protein expression and activity of protein phosphatase 1 (PP1) was evident in the mPFC of<jats:italic>ATRX<\/jats:italic><jats:sup>\u0394<jats:italic>E2<\/jats:italic><\/jats:sup>mice. In cultured cortical neurons, PP1 inhibition by okadaic acid increased CaMKII-dependent Tiam1 and kalirin-7 phosphorylation. Together, our data strongly suggest that aberrant CaMKII activation likely mediates abnormal spine formation in the mPFC. Such morphological changes plus elevated Rac1-GEF\/PAK signaling seen in<jats:italic>ATRX<\/jats:italic><jats:sup>\u0394<jats:italic>E2<\/jats:italic><\/jats:sup>mice may contribute to mental retardation syndromes seen in human patients.<\/jats:p>","DOI":"10.1523\/jneurosci.4816-10.2011","type":"journal-article","created":{"date-parts":[[2011,1,5]],"date-time":"2011-01-05T17:27:57Z","timestamp":1294248477000},"page":"346-358","source":"Crossref","is-referenced-by-count":64,"title":["Aberrant Calcium\/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in the<i>ATRX<\/i>Mutant Mouse 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