DISC1 is a strong candidate susceptibility gene for schizophrenia, bipolar disorder, and depression. Using a mouse strain carrying an endogenous Disc1 orthologue engineered to model the putative effects of the disease-associated chromosomal translocation we demonstrate that impaired Disc1 function results in region-specific morphological alterations, including alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings at CA3/CA1 synapses revealed a deficit in short-term plasticity. Using a battery of cognitive tests we found a selective impairment in working memory (WM), which may relate to deficits in WM and executive function observed in individuals with schizophrenia. Our results implicate malfunction of neural circuits within the hippocampus and medial prefrontal cortex and selective deficits in WM as contributing to the genetic risk conferred by this gene.bipolar disorder ͉ gene ͉ mouse model ͉ working memory ͉ adult neurogenesis

Disrupted-In-Schizophrenia (DISC1) is a leading candidate schizophrenia susceptibility gene. Here, we describe a deletion variant in mDisc1 specific to the 129S6͞SvEv strain that introduces a termination codon at exon 7, abolishes production of the full-length protein, and impairs working memory performance when transferred to the C57BL͞6J genetic background. Our findings provide insights into how DISC1 variation contributes to schizophrenia susceptibility in humans and the behavioral divergence between 129S6͞SvEv and C57BL͞6J mouse strains and have implications for modeling psychiatric diseases in mice.animal model ͉ gene mutation ͉ psychiatric disorder ͉ schizophrenia S chizophrenia is a common and genetically complex psychiatric disorder. Several leading candidate susceptibility genes have been identified (1), including DISC1. The position of this gene was initially pinpointed by a balanced translocation (1;11)(q42.1;q14.3) that was strongly linked to major neuropsychiatric diseases, including schizophrenia, depression, and bipolar disorder in a large Scottish family. The 1q breakpoint involves two genes, DISC1 and DISC2 (a noncoding, presumably regulatory RNA) (2) and truncates DISC1 immediately after exon 8. More recent large-scale linkage and follow-up association studies in families from Finland identified DISC1 as a positional candidate gene from the 1q42 locus (3). In addition, several polymorphisms in DISC1 were reported to be associated with schizophrenia-related cognitive endophenotypes (4 -6). Although the function of DISC1 is poorly understood, the gene is expressed the highest during early development, is associated with numerous cytoskeletal proteins, and could be involved in cell migration and neurite outgrowth and could play a role in centrosomal, microtubule and mitochondrial function, as well as in phosphodiesterase signaling (7-9). ResultsIn the process of a gene targeting experiment at the mDisc1 locus (see Supporting Methods, which is published as supporting information on the PNAS web site), we identified a 25-bp deletion in exon 6 of the 129S6͞SvEv mDisc1 allele. We used RT-PCR of mouse brain RNA from 129S6͞SvEv (Taconic Farms) and C57BL͞6J (The Jackson Laboratory) strains to examine sequences surrounding all mDisc1 exons. We confirmed the 25-bp deletion in exon 6 of 129S6͞SvEv mDisc1 transcript. The deletion was absent in the C57BL͞6J strain ( Fig. 1 a and b). We also confirmed by direct sequencing the presence of this deletion in genomic DNA isolated from tails of Taconic 129S6͞SvEv mice, as well as from ES cells (data not shown). We therefore conclude that this deletion represents a natural 129S6͞SvEv-specific polymorphism. As a control, we amplified exon 6 from genomic DNA from five other inbred strains (BALB͞cJ, CBA͞J, C3H͞HeJ, DBA͞2J, and AKR͞J strains). We did not detect this deletion variant in any strain (Fig. 1c), although we found that BALB͞cJ and C3H͞HeJ strains harbor a single, nonconservative (Glu529His) nucleotide polymorphism within the same 25-bp region. The identified 2...

Mouse models that recapitulate the full phenotypic spectrum of a psychiatric disorder, such as schizophrenia, are impossible. However, a more piecemeal recreation of phenotypic components is feasible and promises to harness the power of animal models using approaches that are either off limits or confounded by drug treatment in humans. In that context, animal models will have a central and indispensable role in the process of discovering the causes of psychiatric disorders and generating novel, mechanism-based treatments. Here, we discuss current approaches used to generate animal models of psychiatric disorders, address the different components of these disorders that can be modeled in animals, and describe currently available analytical tools. We also discuss accumulating empirical data and take an in-depth look at what we believe to be the future of animal models made possible by recent advances in psychiatric genetics.

Emotivist perspectives on moral reasoning hold that emotional reactions precede propositional reasoning. Published findings indicate that, compared with health vegetarians, those who avoid meat on moral grounds are more disgusted by meat [Psychol. Sci. 8 (1997) 67]. If, as per emotivist perspectives, such disgust precedes moral rationales for meat avoidance, then the personality trait of disgust sensitivity should generally be inversely related to meat eating. We surveyed 945 adults regarding meat consumption, reasons for meat avoidance, and disgust sensitivity. Contrary to the emotivist prediction, (a) meat consumption was positively correlated with disgust sensitivity, and (b) individuals who reported avoiding meat for moral reasons were not more sensitive to disgust than those who avoided meat for other reasons. We conclude that moral vegetarianism conforms to traditional explanations of moral reasoning, i.e. moral vegetarians' disgust reactions to meat are caused by, rather than causal of, their moral beliefs. q

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.