Cognition in mouse models of schizophrenia susceptibility genes

Abstract

Cognitive deficits are core features of psychiatric disorders and contribute substantially to functional outcome. It is still unclear, however, how cognitive deficits are related to underlying genetic liability and overt clinical symptoms. Fortunately, animal models of susceptibility genes can illuminate how the products of disease-associated genetic variants affect brain function and ultimately alter behavior. Using as a reference findings from the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia program and the SchizophreniaGene database, we review cognitive data from mutant models of rare and common genetic variants associated with schizophrenia.

Fig. 1.

Animal Models of the DISC1 Locus. Top: chromosomal location and genetic structure of the human DISC1 locus. The t(1;11) translocation break point occurs between exons 8 and 9 (arrow) with exons 9–13 (black) relocated to chromosome 11. Above it are the allele symbols and transgenic constructs based on the human DISC1 gene used to model the functional effects of the translocation. These models interfere with endogenous mouse Disc1 function in a dominant negative manner. Bottom: syntenic chromosomal location and genetic structure of the mouse Disc1 locus and the corresponding break point location (arrow). Below it are 5 of the Disc1 alleles so far described in mice. Disc1^del arose from a spontaneous 25–base pair (bp) deletion within exon 6 that introduces a premature stop codon in exon 7 (TGA) of 129 and related strains of mice. Disc1^tm1Kara was engineered to carry a premature stop codon at the end of exon 8 (TGA) followed by a polyadenylation signal in an attempt to recapitulate the translocation, but because this was created in a 129S6/SveV background the allele also carries the endogenous 25–bp deletion. Disc1^Rgsc1390 and Disc1^Rgsc1393 carry missense mutations in exon 2.

Fig. 2.

Animal Models of the 22q11.2 Locus. Left: chromosomal location and genetic organization of the 22q11.2 locus. Each closed circle represents one gene. This 1.5-megabase critical region is flanked by low-copy repeat sequences (gray boxes) making it prone to nonhomologous recombination. PRODH-P and DGCR6-like are pseudogenes. Right: syntenic region of mouse chromosome 16 and the genetic organization of the corresponding orthologs. Single-gene deletion models that have been analyzed within the relevant CNTRICS cognitive domains are indicated with open circles. Various multigene deletion models that have been cognitively characterized and are discussed in the main text are also shown. The official allele symbols for the models are Lgdel, Del(Dgcr2-Hira)1Ra; Df(16)A, Del(Dgcr2-Hira)2Aam; Df1, Del(16Es2el-Ufd1l)217Bld; and Smdel, Del(16Zpf520-Slc25a1)1Awb.