Researchers Reverse Cognitive and Behavioral Deficits in New Mouse Model for Schizophrenia

Researchers Reverse Cognitive and Behavioral Deficits in New Mouse Model for Schizophrenia

Posted: May 5, 2016

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Takeaway: People with schizophrenia and an associated genetic variation in the NRG1 gene have high levels of a neuronal regulator called NRG1-IV in the brain. Mice whose brains produce human NRG1-IV exhibit schizophrenia-like behaviors, but drug treatment that blocks a NRG1-IV-regulated protein can reverse these symptoms.

Researchers have developed a new model for studying schizophrenia by genetically engineering mice that produce high levels of a human protein, NRG1-IV, in the brain. NRG1-IV, a protein that helps control the development and function of neurons, is overabundant in the brains of people with the schizophrenia who have a specific genetic variant in the NRG1 gene.

A team of scientists led by Amanda J. Law, Ph.D., at the University of Colorado, Denver, School of Medicine, reported April 27, 2016 in the Journal of Neuroscience that mice with human NRG1-IV in the brain exhibit behaviors, cognitive deficits, and neuronal signaling abnormalities that resemble those associated with schizophrenia. The researchers were able to correct many of these problems, in adult mice, by blocking signaling of a protein called p110 delta, whose levels rise when NRG-IV is present.

Dr. Law is a 2006 NARSAD Young Investigator, 2011 Sidney R. Baer, Jr. Prizewinner, and BBRF Scientific Council member. The research team also included 2015 Independent Investigator Francesco Papaleo, Ph.D., at the Italian Institute of Technology; 1999 Young Investigator Jingshan Chen, M.D., Ph.D., at the National Institute of Mental Health; and 1990 and 2000 Distinguished Investigator, 1993 Lieber Prizewinner, and BBRF Scientific Council member Daniel R. Weinberger, M.D., at the Lieber Institute for Brain Development.

The researchers showed that in mice, NRG1-IV alters the balance of excitatory and inhibitory signals in the brain—an imbalance also seen in people with schizophrenia. The protein also interfered with neuronal development, reducing the density of communication junctions, called synapses, between neurons. Mice with NRG1-IV exhibited problems with learning, memory, and social interactions.

Further studies of the new mouse model could help researchers sort out exactly how excess NRG1-IV causes these disruptions. Dr. Law and her colleagues have already linked NRG1-IV and its receptor, ErbB4, to alterations in a signaling pathway called PI3K. Treatment with a drug that blocks p110 delta, a component of the PI3K pathway, reversed behavioral and cognitive deficits (but not social impairments) in adult mice with NRG1-IV. The findings further support the idea that targeting the PI3K pathway could be a useful strategy for treating schizophrenia and associated cognitive deficits, the researchers say.