Transgenic mice with inducible expression of mutant human DISC1 (hDISC1) limited to forebrain regions, including cerebral cortex, hippocampus and striatum were generated using the TET-off gene expression system under the regulation of the CAMKII promoter. Expression of mutant hDISC1 was not associated with gross neurodevelopmental abnormalities, but did produce mild abnormalities. Compared to their sex-matched littermate controls, mutant hDISC1 transgenic male mice exhibited spontaneous hyperactivity in the open field and alterations in social interaction, and transgenic female mice showed deficient spatial memory. Neuronal and behavioral effects of mutant hDISC1 are consistent with a dominant-negative mechanism, and are similar to some features of schizophrenia.
Technical Details:
A strong candidate gene for schizophrenia and major mental disorders, disrupted-in-schizophrenia 1 (DISC1) was first described in a large Scottish family in which a balanced chromosomal translocation segregates with schizophrenia and other psychiatric illnesses. DISC1 has been implicated in neurodevelopment, including maturation of the cerebral cortex. The translocation mutation may result in loss of DISC1 function via haploinsufficiency or dominant-negative effects of a predicted mutant DISC1 truncated protein product.
Looking for Partners:
The mouse model could be used to study of aspects of the pathogenesis and preclinical experimental therapeutics of schizophrenia.
