Deletion or duplication of the human chromosome 22q11.2 is associated with many behavioral traits and neuropsychiatric disorders, including autism spectrum disorders and schizophrenia. However, why phenotypes vary widely among individuals with identical deletions or duplications of 22q11.2 and which specific 22q11.2 genes contribute to these phenotypes are still poorly understood. Previous studies have identified a approximately 200 kb 22q11.2 region that contributes to behavioral phenotypes in mice. We tested the role of Septin 5 (Sept5), a gene encoded in the approximately 200 kb region, in affective behaviors, cognitive capacities and motor activity. To evaluate the impact of genetic backgrounds on behavioral phenotypes of Sept5 deficiency, we used mice on two genetic backgrounds. Our data show that Sept5 deficiency decreased affiliative active social interaction, but this phenotypic expression was influenced by genetic backgrounds. In contrast, Sept5 deficiency decreased anxiety-related behavior, increased prepulse inhibition and delayed acquisition of rewarded goal approach, independent of genetic background. These data suggest that Sept5 deficiency exerts pleiotropic effects on a select set of affective behaviors and cognitive processes and that genetic backgrounds could provide an epistatic influence on phenotypic expression.

Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

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Human chromosome 22q11.2 has been implicated in various behavioral abnormalities, including schizophrenia and other neuropsychiatric͞behavioral disorders. However, the specific genes within 22q11.2 that contribute to these disorders are still poorly understood. Here, we show that an Ϸ200-kb segment of human 22q11.2 causes specific behavioral abnormalities in mice. Mice that overexpress an Ϸ200-kb region of human 22q11.2, containing CDCrel, GP1B␤, TBX1, and WDR14, exhibited spontaneous sensitization of hyperactivity and a lack of habituation. These effects were ameliorated by antipsychotic drugs. The transgenic mice were also impaired in nesting behavior. Although Tbx1 has been shown to be responsible for many physical defects associated with 22q11.2 haploinsufficiency, Tbx1 heterozygous mice did not display these behavioral abnormalities. Our results show that the Ϸ200-kb region of 22q11.2 contains a gene(s) responsible for behavioral abnormalities and suggest that distinct genetic components within 22q11.2 mediate physical and behavioral abnormalities.22q11 ͉ habituation ͉ hyperactivity ͉ mouse model ͉ schizophrenia T he genetic abnormality in 22q11.2 is better delineated than those of most human chromosomal loci that have been implicated in neuropsychiatric and behavioral disorders. Higherthan-expected rates of schizophrenia and other neuropsychiatric disorders are seen in adult patients with 1.5-to 3-Mb haploinsufficiency (i.e., deletion) in 22q11.2 (1-7). Reciprocal duplication of the same chromosomal region also has been identified, and these individuals exhibit impulsivity, aggression, oppositional defiant disorder, social immaturity, short attention spans, attention deficit disorder, and cognitive deficits (8)(9)(10)(11)(12). Because most of these individuals are infants or children at present, their neuropsychiatric disorders have not been fully characterized. However, preliminary data show that individuals with duplications also suffer from neuropsychiatric disorders (9, 12).It remains poorly understood precisely how a gene or set of genes within 22q11.2 contributes to these behavioral phenotypes. In non-duplication͞deletion cases, polymorphisms of various genes residing in 22q11.2 have been associated with schizophrenia and related behavioral and cognitive defects (13,14). For example, a high activity allele of catechol-O-methyl-transferase (COMT) is associated with a heightened risk for schizophrenia in humans (15). As for 22q11.2 deletion cases, haploinsufficiency is associated with prepulse inhibition (PPI) deficits in humans (16), and a comparable deficit is seen in mice with a relatively large 1-Mb heterozygosity, including 19 genes of the mouse synteny of human 22q11.2 (17). Mice defective for either Prodh (proline dehydrogenase) or Zdhhc8 (zinc finger, DHHC-type containing 8) exhibit much weaker PPI deficits (18,19). Given the presumed polygenetic nature of neuropsychiatric disorders and the weak PPI deficits observed in Prodh-and Zdhhc8-deficient mice, it is likely that other 22q11.2 genes cont...