New research suggests that cognitive and behavioral symptoms of schizophrenia may stem at least in part from elevated levels of an enzyme called STEP, which is also thought to be overactive in the brains of people with Parkinson’s disease and Alzheimer’s disease. Experiments in cells collected from patients and in animals suggest that blocking the STEP enzyme, which acts on the connections between neurons to influence their communication, may be an effective future strategy for treating schizophrenia.
In an October 18 publication of the journal Molecular Psychiatry, a team of researchers led by Kristen Brennand, Ph.D., a 2012 NARSAD Young Investigator and 2016 Independent Investigator at the Icahn School of Medicine at Mount Sinai, and Paul J. Lombroso, M.D., Ph.D., a 1993, 2001, and 2003 Independent Investigator and 2006 Distinguished Investigator at Yale School of Medicine, report that blocking the STEP enzyme alleviates schizophrenia-like behaviors in animal models of the disorder.
The team also demonstrated that blocking STEP reversed defects in neurons derived from the cells of patients with schizophrenia. Also part of the team were: Jian Xu, Ph.D., of Yale University and first author on the paper; Swapnil Gupta, M.D., a 2013 Young Investigator at Yale School of Medicine; Judith L. Rapoport, M.D., a 2009 Distinguished Investigator, BBRF Scientific Council Member, and 2002 Ruane Prizewinner at the National Institute of Mental Health; Christopher Pittenger, a 2007 and 2009 Young Investigator and 2015 Independent Investigator at Yale University; and Angus C. Nairn, Ph.D., a 1999 Independent Investigator and 2006 Distinguished Investigator at Yale School of Medicine.
Although the STEP gene has not been found to be mutated in patients with schizophrenia, high levels of the STEP enzyme have been observed in the brains of people with the disorder after their deaths. To investigate the enzyme’s role in the disorder, Drs. Brennand and Lombroso and their colleagues tested the effects of switching STEP off in mice that, due to genetic mutations, mimic many aspects of schizophrenia. Genetically or chemically inhibiting the STEP enzyme in these animal models improved the animals’ memory and cognitive function and restored normal behaviors, such as social interactions and activity patterns.
The researchers also studied human neurons that had been created by reprogramming skin cells from patients with the disorder, so they would have the patients’ exact genetic makeup. STEP levels were higher than normal in neurons derived from about half of the 13 patients who had donated cells. Inhibiting the enzyme in those neurons corrected some of their biochemical deficits and abnormal firing patterns.
The findings suggest that researchers may be able to treat the symptoms of schizophrenia in some patients by developing drugs that inhibiting the STEP enzyme.