Autism is a disorder that offers few clues about its origin; however, recent reports suggest mutations in neuroligin, a protein important in synapse development, are linked to a predisposition to the disease.
Researchers at Columbia have now discovered how neuroligin partners with other proteins to trigger the construction of the presynapse, the side of the synapse that releases neurotransmitters. The new findings, published in the July issue of Nature Neuroscience, shed more light on how synapses are born, a relatively unexplained process. A better understanding of how synapses are made, and unmade, could eventually lead to therapies for paralysis patients, who need new synapses, and autism patients, who appear to have too many.
In the study, Dr. Peter Scheiffele, assistant professor of physiology & cellular biophysics at P&S, postdoctoral researcher Dr. Francisco Scholl, and colleagues at Berkeley found that the presynapse starts to develop after neuroligin binds to neurexins.
The research may lead to a better understanding of how neurons pick their synaptic partners. As the human brain develops, 1 trillion neurons are born and then connect to form 1 quadrillion (1015) synapses. Neurons do not make connections randomly, but it is not known how they select a synaptic partner from a large number of potential candidates.
Selectivity could be controlled by protein families that have large numbers of members, each slightly different from each other. With approximately 1,000 different isoforms, the neurexins are one such family. The role of neurexins in neuron selectivity is still unknown, but the new findings show that neurexins are at least located in the right place during synapse formation to do the job.
Synapses, the points where nerve impulses pass from one neuron to another, are not static entities. Even after they are made, synapses constantly undergo change, becoming stronger, weaker or even disappearing altogether.
P&S researchers recently found that neuregulin-1 keeps synapses between some neurons intact by mediating back-and-forth communication between the two neuronal partners. Without this bi-directional signaling, the synapses degenerate and neurons die. The research was published in the June 23 issue of the Journal of Cell Biology and featured in news highlights in Nature Reviews Neuroscience.
Neuregulin-1 was known previously to promote differentiation of the postsynaptic side of the synapse. But Drs. Lorna Role and David Talmage noticed that the survival of the presynaptic neuron, the side supplying the neuregulin, depended on neuregulin expression. This suggested that neuregulin might send signals in two directions, forward into the neighboring cell and backward into its own cell.
The new research shows how the previously unknown back signal works. After neuregulin initiates the forward signal across the synapse, an intracellular piece of the molecule breaks off and travels to the nucleus of the presynaptic cell. With the help of other molecules, the intracellular domain of neuregulin represses the transcription of cell death genes and keeps the nerve cell alive.
The results suggest that drugs that initiate the back signal may prevent the death of these neurons in neurodegenerative diseases. Dr. Talmage, associate professor of pediatrics and in the Institute of Human Nutrition at P&S, is currently looking for small molecules than can stimulate back signaling. Columbia has a patent on the type of neuregulin involved in the bi-directional signaling (there are 14 different isoforms produced from the neuregulin-1 gene). Neuregulin-1 was also identified in 2002 as a susceptibility gene for schizophrenia.
Columbia researchers, working with community groups and physicians, successfully raised immunization coverage rates for children under age 3 in Northern Manhattan during the late 1990s, according to a recent study in the American Journal of Public Health.
The collaborative effort, called the Northern Manhattan Immunization Partnership, made the first strides in reducing the gap between Northern Manhattan immunization rates and those for New York City overall and the nation. Between 1996, when the program started, and 1999, immunization coverage rates in Northern Manhattan increased five times faster than those of New York City and eight times faster than in the United States, says Dr. Sally E. Findley, professor of clinical population & family health (in pediatrics) at the Mailman School of Public Health and the first author of the paper in the July issue of the journal. Previous attempts to raise coverage rates by either physicians or community groups were largely ineffective.
The Columbia program, which includes researchers from both the Mailman School and P&S, is unusual in that it involves networks of physicians and community groups, working in partnership to reach all children under age 3 in Northern Manhattan. The program grew to include 26 physician practices and 20 community groups by 1999, when a related community-based program, Northern Manhattan Start Right Coalition, was launched. The researchers worked with physicians to develop better tracking documentation to ensure that children received the shots they needed. The investigators also conducted semi-annual medical chart audits for randomly selected children in the doctors' offices. "That way it's hard for the physicians to say it's somebody else's problem," Dr. Findley says.
The investigators also helped community groups increase their outreach efforts to educate parents. Though parents hear about immunizations from their doctors, they say they never fully understood until the community health worker explained using pictures and sharing their own experiences, Dr. Findley says. The coalition also empowers parents to request immunizations any time they go to the doctor, without waiting to make a special appointment.