In a new genetic study by researchers at Johns Hopkins University, including NARSAD Grantees Hanna Jaaro-Peled, Ph.D. and Akira Sawa, M.D., Ph.D., elevated levels of oxidative stress in the prefrontal cortex were linked to cognitive and motivational impairments in mice with a mutated version of DISC1 (the ‘disrupted in schizophrenia 1’ gene, long thought to be linked to susceptibility for schizophrenia and other mental illnesses). The research was published online July 9, 2013 in the Proceedings of the National Academy of Sciences.

Dysfunctions in the prefrontal cortex, the part of the brain responsible for cognitive and emotional control, have been linked to cognitive impairments in patients with major mental illness, including schizophrenia and mood disorders. The researchers hypothesized that these defects could be caused by vulnerability of the cells in the central nervous system to oxidative stress. Oxidative stress is caused by an imbalance in highly reactive molecules in the body that can damage DNA and proteins.

In the study, genetically-engineered mice performed certain learning tasks that were associated with a reward. The research team found that the mice with a mutated version of DISC1 showed behavioral impairments associated with prefrontal-dependent tasks, including both cognitive and motivational deficits. To test if these behavioral deficits were caused by oxidative stress, the team measured the levels of a conversion of an enzyme called GAPDH (glyceraldehyde 3-phosphate dehydrogenase) as a sensor of oxidative stress. In typical physiological conditions, GAPDH is involved in glycolysis, the complex metabolic process that utilizes glucose for energy. In contrast, in pathological conditions, GAPDH is converted and translocates to the nucleus and acts as a sensor for oxidative stress. The nuclear, converted GAPDH has been found to play a role in regulating epigenetics, or the process through which environmental factors affect the expression of genes without altering the underlying DNA.

The research team detected elevated levels of the conversion of GAPDH in the prefrontal cortex of these transgenic mice, thus providing the first evidence for a link between oxidative stress, disrupted connectivity in the prefrontal cortex and cognitive and motivational impairments. Because DISC1 is implicated in a wide range of mental illnesses, this animal model offers a new approach to study pathogenesis in schizophrenia and other mental illnesses associated with prefrontal dysfunction as well as a way to test new treatments. The research team has already filed a patent on a novel compound that can block this conversion of GAPDH that is expected to be a novel treatment strategy for major mental illness.