ABSTRACT

Doublecortin (DCX) is a microtubule-associated protein that is required for normal neocortical and hippocampal development in humans. Mutations in the X-linked human DCX gene cause gross neocortical disorganization (lissencephaly or "smooth brain") in hemizygous males, whereas heterozygous females show a mosaic phenotype with a normal cortex as well as a second band of misplaced (heterotopic) neurons beneath the cortex ("double cortex syndrome"). We created a mouse carrying a targeted mutation in the Dcx gene. Hemizygous male Dcx mice show severe postnatal lethality; the few that survive to adulthood are variably fertile. Dcx mutant mice show neocortical lamination that is largely indistinguishable from wild type and show normal patterns of neocortical neurogenesis and neuronal migration. In contrast, the hippocampus of both heterozygous females and hemizygous males shows disrupted lamination that is most severe in the CA3 region. Behavioral tests show defects in context and cued conditioned fear tests, suggesting that deficits in hippocampal learning accompany the abnormal cytoarchitecture.

No abstract

Velocardiofacial/DiGeorge syndrome (VCFS/DGS) is a developmental disorder caused by a 1.5 to 3-Mb hemizygous 22q11.2 deletion. VCFS/DGS patients display malformations in multiple systems, as well as an increased frequency of neuropsychiatric defects including schizophrenia. Haploinsufficiency of TBX1 appears to be responsible for these physical malformations in humans and mice, but the genes responsible for the neuropsychiatric defects are unknown. In this study, two mouse models of VCFS/DGS, a deletion mouse model (Lgdel/+) and a single gene model (Tbx1 +/-), as well as a third mouse mutant (Gscl -/-) for a gene within the Lgdel deletion, were tested in a large behavioral battery designed to assess gross physical features, sensorimotor reflexes, motor activity nociception, acoustic startle, sensorimotor gating, and learning and memory. Lgdel/+ mice contain a 1.5-Mb hemizygous deletion of 27 genes in the orthologous region on MMU 16 and present with impairment in sensorimotor gating, grip strength, and nociception. Tbx1 +/- mice were impaired in grip strength similar to Lgdel/+ mice and movement initiation. Gscl -/- mice were not impaired in any of the administered tests, suggesting that redundant function of other Gsc family members may compensate for the loss of Gscl. Thus, although deletion of the genes in the Lgdel region in mice may recapitulate some of the behavioral phenotypes seen in humans with VCFS/DGS, these phenotypes are not found in mice with complete loss of Gscl or in mice with heterozygous loss of Tbx1, suggesting that the neuropsychiatric and physical malformations of VCFS/DGS may act by different genetic mechanisms.

Dvl1 is one of three murine Dishevelled genes widely expressed in embryonic development and in the adult central nervous system. Dishevelled proteins are a necessary component of the Wnt and planar cell polarity developmental signaling pathways. We reported previously that mice deficient in Dvl1 exhibited abnormal social interaction and sensorimotor gating. To assess the validity of our earlier findings, we replicated the previous behavioral tests and included several new assays. The behaviors assessed included: social interaction, sensorimotor reflexes, motor activity, nociception, prepulse inhibition of acoustic startle (PPI) and learning and memory. Assessments with an explicit social component included: social dominance test, whisker trimming, nest building, homecage huddling and ultrasonic vocalization rate analysis in pups. In addition, separate cohorts of wildtype and Dvl1-null mice were assessed for social recognition of a conspecific. Replicating the original report, Dvl1-null mice were impaired in several tasks containing an explicit social component. However, no impairment was observed in the social memory task. A previously observed deficit in PPI did not replicate in two institutions. In conclusion, we provide evidence that the social interaction phenotype of Dvl1-deficient mice has a strong genetic influence, but the sensorimotor gating deficit was subject to environmental influences. The specificity of observed social interaction deficits also suggests that lack of Dvl1 is associated with deficits in the recognition of social hierarchy and dominance.