Science Update • March 18, 2009

New Silvio O. Conte Centers Address Brain Development, Disorders

With a mandate to use innovative, multidisciplinary research approaches to address important mental health questions, four newly funded centers have begun investigations of schizophrenia, brain development, and adolescent mood disorders. The four are the latest among NIMH's Silvio O. Conte centers, all of which have as their goal bringing together diverse expertise and cutting edge technology to gain new knowledge and improve the diagnosis and treatment of mental health disorders.

Since 1988, NIMH has encouraged scientists to seek funding for projects in which a unifying, well-defined scientific question would be approached from many angles and at many levels (for example, genetic, molecular, clinical, and behavioral) via its Centers for Neuroscience of Mental Disorders and Centers for Neuroscience Research. In 1993, these centers were renamed in memory of Rep. Silvio O. Conte, a champion of neuroscience research and the severely mentally ill. In keeping with the guidelines for Conte Centers, each of the four recently funded centers must be capable of conducting cutting edge research, with an eye for translation of basic research findings to mental health:

• Scientists at the University of Pittsburgh and Carnegie Mellon University are investigating the origins of cognitive deficits in schizophrenia. Problems with cognition are consistently present in schizophrenia, and while they may not be as dramatic as disordered perception, they are disabling. Research suggests that altered activity in a subset of neurons using the neurotransmitter GABA as the primary signaling molecule, may play a role these deficits. Center scientists will look for GABA-related gene products associated with changes in brain wave patterns seen in schizophrenia. Brain waves reflect the synchronized firing of neurons, which in turn underlie cognitive processes. The scientists will also test pharmacological agents to see if they restore normal GABA signaling. The project requires the participation of experts in disciplines as wide-ranging as neuroanatomy, electrophysiology, microscopy, state-of-the-art functional and structural imaging, computer modeling, and clinical neuroscience. The ultimate goal is to identify, based on knowledge of the underlying brain chemistry, novel treatments as well as biomarkers—features of biologic processes that can be used to assess function. Dr. David Lewis is the principal investigator at this center.
• Scientists at a Conte center at Johns Hopkins University aim to clarify exactly how changes in genetic susceptibility factors for schizophrenia regulate the development of the nervous system. Research suggests that schizophrenia alters developmental processes in the brain well before symptoms of the disease emerge in early adulthood. One key susceptibility factor, the protein DISC1, is reported to be a central player in such processes as the formation of synapses, the regulation of cell division, and the growth of new neurons in adulthood. This group will explore interactions of proteins involved in DISC1 molecular pathways. Genetic studies will identify genes related to the developmental cascades identified. The investigators will generate mice with targeted genetic changes and observe any behavioral effects. Elucidating the chain of events between gene products and disease will provide an information base for developing new and earlier interventions. Dr. Akira Sawa is the principal investigator.
• Scientists at another Conte center at Johns Hopkins University are studying the biochemistry and genetics behind how the brain responds to experience. Brain cells communicate with each other using chemical and electrical signaling between cells at specialized junctions called synapses. Long-term changes in the efficiency of this chemical and electrical signaling and associated changes in the configuration of synapses are thought to underlie brain development, the learning process, and changes in cognitive function in health and in disease. Scientists at this center will identify the molecular mechanisms involved in synapse formation, how signaling events at the synapse influence subsequent gene expression in the nucleus, and how these changes result in further long-lasting changes at synapses. Many of the drugs that are effective for treating mental health disorders are known to target synapses; further, malfunctions of synaptic mechanisms are implicated in disorders of cognition such as autism and schizophrenia. This work will help clarify the processes involved in normal communication among brain cells, and pave the way for identifying the mechanisms that go awry in mental health disorders. Dr. Richard Huganir is the principal investigator.
• The focus of the Conte center at the University of Wisconsin-Madison is a more complete understanding of the biologic and behavioral risk factors for anxiety and mood disorders in adolescence. The risk of adult anxiety and depressive disorders is substantially increased in adults who had symptoms in adolescence. Scientists at this center will study groups of adolescents, gathering detailed information on behavior, family environment, and any signs of mood disorders; levels of brain stress hormones, which can be both indicators of how the brain reacts to stress and markers of vulnerability to mood disorders; and structural and functional information from imaging studies on parts of the brain involved in emotional responses. Information on the dynamics of early stress, behavior, and the brain should provide insight into the variability of these disorders, risk factors for developing them, and possible treatment approaches. Dr. Richard Davidson is the principal investigator at this Conte center.

As research progresses, greater specialization is required to understand the complexities of biologic systems. Conte centers offer a context in which scientists can collaboratively address this complexity and translate the resulting knowledge into new methods of diagnosis and treatment.