Studies of how brain cell communication may be altered in schizophrenia have earned Dr. Lin Mei, chief of developmental neurobiology at the Medical College of Georgia, a 2008 Distinguished Investigator Award from NARSAD.
Dr. Mei, Georgia Research Alliance Eminent Scholar in Neuroscience and professor in the MCG School of Medicine's Department of Neurology, is one of 11 scientists to receive the award, which includes a $100,000 one-year grant from the world's leading charity dedicated to mental health research.
He has found that two genes, important for human development and implicated in other disorders including cancer and seizures, normally enable a healthy balance of brain cell excitation and inhibition. In 2007, Dr. Mei's lab showed neuregulin-1 and its receptor, ErbB4, promote inhibition at the site of inhibitory synapses in the brain by increasing release of GABA, a major inhibitory neurotransmitter. Seven years earlier, he led a team that showed that the gene pair suppresses synapses between neurons where the neurotransmitter glutamate excites cells to action. "According to our model, it inhibits," Dr. Mei says of neuregulin-1.
Schizophrenia has been labeled a degenerative disease where neurons die and a developmental disease where the wiring is laid wrong. Dr. Mei's research shows problems in neuron communication, likely also are to blame. "It's a complex disease," says Dr. Mei in which neuregulin-1 expression is off balance, possibly the result of mutations in the neuregulin-1 gene.
He believes even a subtle imbalance in brain cell excitation and inhibition helps explain the cognitive problems in schizophrenia and possibly other disease hallmarks of hallucinations and social disconnection. He also believes that correcting the imbalance is doable. "Say neurotransmission is high: you could try to suppress it. If low, you could try to stimulate it."
Dr. Mei already has inhibitors and activators in his lab refrigerator. They aren't clinical-grade but have helped him illustrate what happens when neuregulin-1 activity goes up or down. One of his many goals is to identify small molecules, which are soluble, deliverable and would similarly manipulate neuregulin function. "You would hope they would be like aspirin: easily deliverable to the brain," says Dr. Mei.
Neuregulin-1 actually has about six known types, and type I is expressed in higher levels in the pre-frontal cortex of schizophrenics, the portion of the brain critical to cognition, learning and working memory. That 2004 finding by National Institute of Mental Health scientists shifted the focus toward type I and Dr. Mei toward development of an animal model that also expresses high levels of type I neuregulin. Most studies, including his, use models in which the genes are knocked out.
"Knockout models do not mimic what is going on in the patient," says Dr. Mei. A recent $514,000, three-year grant from the National Institute of Mental Health grant will enable him to develop a mouse that may.
Dr. Mei also recently received a $1.6 million, five-year grant from the institute to further study neuregulin-1's regulation of neurotransmission. He wants to know which transcription factors bind to neuregulin-1 to regulate expression and how they do it. He suspects mutated genes change how much binding occurs and, consequently, how much neuregulin is expressed. He also wants to know exactly how neuregulin-1, in turn, controls GABA release, and, ultimately if the resulting signal the neuron sends is determined by neuregulin-1. His work indicates the protein probably does have a powerful role in determining neuron talk.
"Dr. Mei exemplifies the kind of individual we try to single out for the Distinguished Investigator Award: an outstanding scientist, representing the very best in the field, with an important body of work behind him, and currently pursuing innovative and promising research," says Geoff Birkett, NARSAD president.
Dr. Mei also recently received the 2008 Mathilde Solowey Lecture Award in Neurosciences. The annual award, administered by the Foundation for Advanced Education in the Sciences, honors rising neuroscientists who excel in cutting-edge, translational research that is of broad importance. As the award recipient, Dr. Mei will discuss his studies May 15 at the National Institutes of Health in Bethesda, Md.