"We found that when this gene or this pathway is impaired," explained CSHL's Bo Li. "It starts a chain reaction negatively impacting synapses in the brain which contribute to the abnormal development of brain circuits and may lead to schizophrenia."

By discovering the connections between genes and how they impact synapses and circuits in the brain, research is guiding the development of new strategies to diagnose and treat neurological disease. Published on May 24, 2007 in the journal Neuron, this latest research supports the hypothesis that schizophrenia is a disease that results from multiple factors, including genetic defects and developmental abnormalities in the brain. A lynchpin in the development of the disease is the brain's neurotransmitter system known as the glutamate system. When the glutamate system is suppressed it leads to abnormal brain development and schizophrenic symptoms.

Unlocking the mystery of NRG1 and its critical function in the normal development of the glutamate system was the result of a unique combination of technologies at CSHL. Under the direction of CSHL's Neuroscience Research Program Chair, Robert Malinow, M.D., Ph.D., researchers inform their study of diseased brains by the ongoing study of normal brains. "The ability to finally identify the functionality of NRG1 was possible here because of access to powerful technology that combined the ability to manipulate individual genes, to study the very structure of the glutamate synapse with a two-photon microscope, and to perform functional studies using electrophysiology."

Li hopes that his research will stimulate more exploration of the functions of NRG1 in the brain. "This gene and its pathway also have implications for other neurological diseases such as bipolar disorder. Knowing the cellular and molecular mechanisms of NRG1, we can now more intensely study the impact on complex brain circuits that define the aberrant behavior of these diseases," said Li.

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Beyond the current study, Kyrkanides, work has contributed to the emerging theory that pain is not a symptom of osteoarthritis, but is instead part of the disease. According to this new paradigm, pain is composed of nerve messages that over time cause permanent chemical changes in the pathways they travel along, making them more sensitive to pain and encouraging inflammation. This two-way "crosstalk" may mean that arthritis in one joint can spread, through the central nervous system (CNS), to other joints. Worse yet, joint arthritis may export inflammation to the brain, where it plays a role in neurological conditions (e.g. Alzheimer's disease, dementia and multiple sclerosis).

While the just published study involved a technique that delivers gene therapy by injection at the joint, other promising approaches may involve interrupting crosstalk in the brain instead. Based on that promise, the Medical Center is in the process of founding a private biotech company to develop the technology. It would search for new drugs that interfere with key inflammatory receptors on sensory nerve cells within the CNS.

Joining Kyrkanides in the publication from the University of Rochester School of Medicine and Dentistry were co-authors J. Edward Puzas, Ph.D., Donald & Mary Clark Professor of Orthopaedics, M. Kerry O'Banion, M.D., Ph.D., associate professor of Neurobiology and Anatomy and Ross Tallents, D.D.S., professor of Dentistry and director of the Orofacial Pain Program within the University of Rochester's Eastman Dental Center. Student contributors were Paolo Fiorentino, Yanjun Gan, Yu-Ching Lai and Solomon Shaftel. Jennie Miller was involved as Kyrkanides, technical associate. Maria Piancino, of the University of Torino, Italy, was also an author based on an alliance between the two institutions. The study was funded in part by the National Institute of Dental and Craniofacial Research.

"Near future applications of the work may include amplifying the body's response to morphine, drastically reducing the amount needed for powerful pain relief," Tallents said. "A little further out, the new idea that peripheral inflammatory diseases like arthritis can lead to brain inflammation may provide an entirely new way to treat inflammatory neurological conditions that affect millions."

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