Scientists at Johns Hopkins have developed a mouse model for schizophrenia in which a mutated gene linked to schizophrenia can be turned on or off at will.

The researchers developed the transgenic mouse by inserting the gene for mutant Disrupted-In-Schizophrenia-1 (DISC-1) into a normal mouse, along with a promoter that enables the gene to be switched on or off. Mutant DISC-1 was previously identified in a Scottish family with a strong history of schizophrenia and related mental disorders.

The study was performed in the laboratory of Mikhail Pletnikov, M.D., Ph.D., in the Department of Psychiatry and Behavioral Sciences.

Last month, another Hopkins researcher in the Department of Psychiatry and Behavioral Sciences, Akira Sawa, M.D., Ph.D., and his team, developed a comparable mutant DISC-1 mouse model for schizophrenia. Pletnikov’s is the first model in which researchers can control the expression of this mutated gene, and the model illuminates additional aspects of the biology of the disorder.

Researchers turn off the mutant DISC-1 gene by feeding the mice a nontoxic chemical that controls a genetically engineered switch mechanism to turn on production of the DISC-1 protein.

The study, which appears in the September issue of Molecular Psychiatry, showed that male mice with the mutant DISC-1 gene were significantly more active than control mice without the mutated gene. The investigators also observed that the male mutant DISC-1 mice had altered social interactions with other mice and were more aggressive. Females with the mutated gene had a more difficult time remembering how to navigate a maze.

“Schizophrenia is a human disorder, so we cannot say the symptoms displayed by the mouse model are schizophrenic. But they are in line with the kinds of behavioral changes we see in humans with schizophrenia,” says Pletnikov.

The research showed other strong similarities between the mouse model and humans with schizophrenia.

Examination of the brains of the mutated mice using MRI scans showed significant enlargement of the lateral ventricles (fluid-filled areas in the front of the brain), very similar to MRI findings in humans with schizophrenia.

Tissue culture studies showed that there was an abnormality in the development of brain cells in the part of the brain generally associated with schizophrenia. Also, the transgenic mice had abnormal levels of the proteins 25 kDa synaptosome-associated protein (SNAP-25) and lissencephaly-1 (LIS-1).

It’s known from previous research that SNAP 25 and LIS-1 are key players in brain cell development and maturation, and several prior studies of brain tissue from humans with schizophrenia showed abnormal levels of SNAP-25.

“This model supports the idea that schizophrenia is a disease associated with abnormal brain development,” says senior co-author of the study Christopher Ross, M.D., Ph.D., of the Department of Psychiatry and Behavioral Sciences. “And being able to regulate the timing of expression of the mutant protein provides an opportunity to study the timing and mechanism of specific abnormalities -- a tool that could eventually lead to the discovery of drugs that could potentially control or even prevent the disease.”

Additional authors of the study from Johns Hopkins include Yavuz Ayhan, M.D., Olga Nikolskaia, M.D., Yanqun Xu, M.S., and Timothy H. Moran, Ph.D., of the Department of Psychiatry and Behavioral Sciences; and Hao Huang, Ph.D., and Susumu Mori, Ph.D., of the Department of Radiology-Magnetic Resonance Research.

This study was supported by the Stanley Medical Research Institute, a NARSAD Distinguished Investigator Award, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

- Johns Hopkins Medical Institutions