Genetics tells us that abnormal synaptic and nuclear proteins are often at the root of major neuropsychiatric disorders. Autism, a prominent and often debilitating disorder of the brain, has been traced to small contributions of hundreds of genes, creating a formidable challenge for those interested in exploring pathophysiology and possible therapeutic interventions. A major interest of our laboratory is a form of autism known as Timothy Syndrome (TS), which arises from a point mutation in a signaling protein. Though rare, the mutation causes autism spectrum disorder (ASD) with 3:1 odds. The gene, known as CACNA1C, encodes a particular kind of calcium channel known as “L-type”. We have studied the behavior of mice bearing the TS mutation and find persistent behavior, altered communication, and reduced social interaction relative to their unaffected sibs, features reminiscent of the three characteristic hallmarks of autism. The mutation leads to over-activity of the ion channel, raising the prospect that it might be counteracted pharmacologically. Interestingly, the same CACNA1C gene has been repeatedly implicated in schizophrenia and in Major Depressive Disorder. The possibility arises that work on diverse neuropsychiatric diseases will prove more synergistic than previously appreciated.
Why does miscoding in CACNA1C exert such strong effects? Like its close relatives, this particular L-type calcium channel plays a central role in allowing a neuron to track its own activity. In a process called excitation-transcription coupling, neuronal firing drives the opening of the L-type channel, flow of calcium into the cell, activation of transcription factors, and expression of specific sets of genes. Ultimately, this supports neuronal autoregulation and plasticity. We are currently working out critical details of how the L-type channel transmits a packet of information to control nuclear gene transcription. Interestingly, elements of this signaling pathway are encoded by genes that have also been implicated in causing neuropsychiatric disorders.
Disorders at the cellular level are thought to engender aberrant function of neuronal circuits. Oxytocin is a key neuromodulator whose influence on neuronal circuitry has been linked to social memory and maternal behavior in animals, as well trust, emotion recognition and parenting in humans. Multiple clinical trials have uncovered promising actions of oxytocin on autistic behavior in teenagers, including processing of information about faces. By examining oxytocin actions in brain slices, we have found that activation of oxytocin receptors sharpens the responses of a canonical hippocampal circuit. The peptide increases the fidelity of signal transmission through the network, while simultaneously suppressing the noise of background spontaneous activity. These seemingly contradictory actions are both mediated through a selective depolarization of the fast-spiking interneurons by oxytocin. The resulting increase in inhibitory tone in principal cells dampens their spontaneous activity. Meanwhile, a use-dependent depression of the feed-forward inhibitory synapses permits enhanced spike transmission. By activating fast-spiking neurons with cholecystokinin, or with channelrhodopsin-2, we demonstrate that this novel circuit mechanism is generally applicable to any manipulation that elicits the firing of fast-spiking basket cells. We have begun testing the action of oxytocin agonists on reversal learning, to determine if perseverative behavior can be ameliorated. The prospect looms that actions of oxytocin at the circuit level might contribute to its behavioral impact in autistic individuals, but at the moment this is merely a hypothesis.
About the Speaker
Richard W. Tsien, DPhil, is Director of the Neuroscience Institute, Druckenmiller Professor of Neuroscience, and Chair of the Physiology and Neuroscience Department at the NYU School of Medicine. Prior to joining NYU in August 2011, Dr. Tsien served as the George D. Smith Professor of Molecular Genetic Medicine at Stanford University. While there, Dr. Tsien founded and served as the inaugural chair of the Department of Molecular and Cellular Physiology. After a six-year term as chair, in 1994 he co-led a successful Stanford-wide movement to establish an institute for neuroscience, the Stanford Brain Research Center, which he co-directed from 2000 through 2005. He served a 10-year term as the director and principal investigator at Stanford’s Silvio Conte Center for Neuroscience Research. As a scientist, Dr. Tsien is a world leader in the study of calcium channels and their signaling targets, particularly at pre- and postsynaptic sites. He studies how synapses contribute to neuronal computations and network function in both healthy and diseased brains. His research, generously supported by the NIH and private foundations, has contributed substantially to understanding how neurotransmitters, drugs and molecular alterations regulate calcium channels and has implications for diverse clinical areas such as pain and autism. His research has been published in over 200 peer-reviewed journal articles, and he has served on editorial boards for numerous journals. He has also served as section chair for the American Association for the Advancement of Science (Neuroscience Section) and the National Academy of Sciences (Neurobiology Section) and has been a member of scientific advisory boards for several institutes, including the Howard Hughes Medical Institute. Dr. Tsien received both an undergraduate and graduate degree in electrical engineering from the Massachusetts Institute of Technology. He was a Rhodes Scholar, graduating with his doctorate in biophysics from Oxford University, England after which he joined the faculty at Yale University School of Medicine and served for nearly two decades. He is a member of both the Institute of Medicine and National Academy of Sciences. He was awarded the Julius Axelrod Prize by the Society for Neuroscience in 2012.