Gene found to foster synapse formation in the brain

Implications for language development, autism, epilepsy Researchers at Johns Hopkins say they have found that a gene already implicated in human speech disorders and epilepsy is also needed for vocalizations and synapse formation in mice. The finding, they say, adds to scientific understanding of how language develops, as well as the way synapses — the connections among brain cells that enable us to think — are formed. A description of their experiments appears in Science Express on Oct. 31. A group led by Richard Huganir, Ph.D., director of the Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, set out to investigate genes involved in synapse formation. Gek-Ming Sia, Ph.D., a research associate in Huganir's laboratory, first screened hundreds of human genes for their effects on lab-grown mouse brain cells. When one gene, SRPX2, was turned up higher than normal, it caused the brain cells to erupt with new synapses, Sia found. When Huganir's team injected fetal mice with an SRPX2-blocking compound, the mice showed fewer synapses than normal mice even as adults, the researchers found. In addition, when SRPX2-deficient mouse pups were separated from their mothers, they did not emit high-pitched distress calls as other pups do, indicating they lacked the rodent equivalent of early language ability. Other researchers' analyses of the human genome have found that mutations in SRPX2 are associated with language disorders and epilepsy, and when Huganir's team injected the human SRPX2 with the same mutations into the fetal mice, they also had deficits in their vocalization as young pups. Another research group at Institut de Neurobiologie de la Méditerranée in France had previously shown that SRPX2 interacts with FoxP2, a gene that has gained wide attention for its apparently crucial role in language ability. Huganir's team confirmed this, showing that FoxP2 controls how much protein the SRPX2 gene makes and may affect language in this way. "FoxP2 is famous for its role in language, but it's actually involved in other functions as well," Huganir comments. "SRPX2 appears to be more specialized to language ability." Huganir suspects that the gene may also be involved in autism, since autistic patients often have language impairments, and the condition has been linked to defects in synapse formation. This study is only the beginning of teasing out how SRPX2 acts on the brain, Sia says. "We'd like to find out what other proteins it acts on, and how exactly it regulates synapses and enables language development." Roger Clem of the Mount Sinai School of Medicine also participated in the study CADC I & II Continuing Education ### This study was supported by the National Institute of Mental Health (grant number P50MH084020) and the National Institute of Neurological Disorders and Stroke (grant number NS050274). Related stories: Study Refutes Accepted Model of Memory Formation Johns Hopkins Scientists Reveal Molecular Sculptor of Memories Johns Hopkins Researchers Discover How to Erase Memory

NIMH Grantee Receives 2013 Nobel Prize

Congratulations to current NIMH grantee Thomas C. Südhof, M.D., at Stanford University School of Medicine, for winning the Nobel Prize in Physiology or Medicine for his work on how the brain sends and receives chemical messages. Thomas C. Südhof, M.D. Thomas C. Südhof, M.D. Stanford University School of Medicine “We are extremely proud of Dr. Südhof,” said National Institute of Mental Health (NIMH) Director Thomas Insel, M.D. “NIMH has supported Dr. Südhof's ground-breaking research for more than two decades as part of our commitment to understanding the fundamental mechanisms of brain function." The human brain houses about 100 billion neurons—about half the number of stars in the Milky Way. Each of these neurons “converses” with, on average, thousands of other neurons, sending molecular messages in a matter of milliseconds, about the same timeframe as a camera flash. How these messages are sent in such a rapid and precise manner has long been a mystery to neuroscientists. When these messages go awry, mental disorders such as schizophrenia, autism, and depression may arise. Specifically, Dr. Südhof parsed the proteins that are used in a synapse—the gap between neurons where one neuron reaches out to talk to another via chemical messengers known as neurotransmitters. These specialized spaces are comprised of three components: the messenger or presynaptic neuron, the recipient or postsynaptic neuron, and the cleft or space between these two neurons. Dr. Südhof’s work identified key molecules involved in the rapid release of neurotransmitters from the terminals of presynaptic neurons and revealed how electrical signals in the form of calcium ions instruct a protein called synaptotagmin. Once calcium binds to synaptotagmin, the protein serves as a switch for neurotransmitter-carrying cellular shuttles called vesicles to fuse with the outer surface of the presynaptic neuron and release these chemical messengers into the synaptic cleft. Upon release, the neurotransmitters cross the synaptic cleft and bind to docking sites or receptors on the postsynaptic neuron, triggering an electrical signal to pulse through it. Südhof’s work revealed that synaptotagmins also act as universal calcium sensors in non-neuronal cells, functioning, for example, in the release of hormones such as insulin from pancreatic beta cells. Dr. Südhof shares the world’s most prestigious science award with James E. Rothman, Ph.D., at Yale University, and Randy W. Schekman, Ph.D., at the University of California, Berkeley. Dr. Rothman unraveled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Dr. Schekman discovered a set of genes that were required for vesicle traffic. The researchers will share a prize that totals roughly $1.2 million USD. Previously, Dr. Südhof and Richard H. Scheller, Ph.D., at Genentech, collected the 2013 Albert Lasker Basic Medical Research Award for their work. Known as “America’s Nobels,” the Lasker Awards often predict future Nobel Prize recipients. The National Institutes of Health (NIH) has supported Dr. Südhof’s research over the past 22 years. In turn, Dr. Südhof has served on several study sections at the NIH Center for Scientific Review, in addition to the Molecular, Cellular, and Developmental Neuroscience study section at NIMH. Over the years, Dr. Südhof’s work on the neurotransmitter release machinery has been supported with research program grants as well as center grants from NIMH. He is also the recipient of an NIMH MERIT (Method to Extend Research in Time) award, which along with an additional NIMH grant and funding from the Howard Hughes Medical Institute helped support his Nobel work. MERIT awards provide up to 10 years of stable research support for highly productive outstanding investigators working on projects well aligned with the mission of NIMH Social Worker Continuing Education Dr. Südof also holds an NIH TR01 award for work to facilitate the creation of neurons from non-neuronal cells (skin fibroblasts of human patients). This work is anticipated to provide a novel way for scientists to study the biological effects of gene mutations associated with neuropsychiatric diseases