Genetic dissection of nervous system development, function and plasticity
B.Sc., University of Oregon
Ph.D., University of Cambridge (England)
What are the molecular mechanisms underlying coordinated movement, integrated behavior, cognition, learning and memory? How does the nervous system circuitry underlying these behaviors develop, and how are these circuits modified by experience? How do these mechanisms go awry in inherited neurological diseases and age-related neurological decline? These questions center around the common themes of information transfer and information storage in cells of the nervous system. My long-term interest has been to understand the fundamental principles of nervous system development, function and plasticity by applying systematic genetic analyses to address these questions.
The primary focus of my laboratory is on the synapse, the specialized intercellular junction which functions as the communication link between neurons, and between neurons and muscle. Chemical synapses mediate the vast majority of communication in the nervous system and exhibit plastic properties underlying the behavioral and cognitive malleability of the brain. Our experimental approach is to use a combination of forward genetics, reverse genetics and functional genomics to identify synaptic genes, generate mutants and then assay mutant phenotypes to elucidate the function of normal synaptic gene products. Our laboratory uses this strategy to investigate three closely related questions: 1) How do synapses develop?, 2) How do synapses function? and 3) How do synapses maintain adaptive plasticity?
Synaptic development involves specifying and constructing the intercellular communication link. The developmental program specifies synaptic partnerships and aligns the presynaptic signaling apparatus with the postsynaptic receptor field. The mature function of the synapse is to translate electrical information into chemical information and back again. This information transfer requires mechanisms to couple an action potential to the fusion of neurotransmitter vesicles, receipt of the signal by a receptors and downstream signaling pathways. Synaptic plasticity is the key to nervous system adaptability, including higher cognitive functions. Plasticity is the process whereby synaptic form and/or function is altered is response to use, to modulate communication either transiently (learning) or permanently (memory). We screen directly for genetic mutants defective in learning/memory and then assay the roles of the mutant genes at the synapse.
A primary interest is to develop models of human neurological diseases linked to inherited synaptic dysfunction. On-going studies focus a model of Fragile X syndrome (FXS), the most common inherited neurological disease which results in cognitive impairment and autism spectrum disorders. Multiple lines of evidence suggest that FXS is caused by defects in synaptic development and plasticity due to inappropriate translational regulation. We are employing many complementary behavioral, electrophysiological, imaging and molecular genetic approaches to study this important disease state. We are particularly interested in activity-dependent mechanisms and the regulation of inhibitory vs. excitatory synapses in central brain circuits.
Our approach to the synapse is multi-disciplinary and requires the marriage of many traditionally distinct fields. Our work involves classical geneticists, molecular biologists, developmental cell biologists, anatomists and electrophysiologists. In the long term, we hope that this work will lead to a greater understanding of nervous system development and function including neural network formation, mechanisms of integrated neuronal communication, higher brain functions including learning and memory, and the cure for synaptic dysfunction arising in inherited neurological diseases.
We are interested in uncovering the molecular and cellular bases of neurological diseases. We are particularly interested in inherited diseases linked to synaptic dysfunction. Our goal is to generate powerful genetic models of targeted diseases and then use a combination of forward genetics, reverse genetics and genomic/proteomic strategies to elucidate underlying molecular defects.
One example is Fragile X Syndrome, the most common cause of inherited mental retardation. This disease is caused by defects in translation regulation within neurons leading to an arrest in the functional development of synapses. We have generated a simple genetic model of this disease, and shown that the model recapitulates the major major disease symptoms (Zhang et al., Cell 2001). We are now exploiting this model to identify interacting genes and proteins that regulate synaptic differentiation.
Another example is a disparate set of inherited neurodegeneration diseases. Our hypothesis is that neuronal apoptosis may be a secondary consequence of progressively impaired synaptic transmission required to maintain cell viability. We are working with both "protein storage diseases" (e.g. Parkinson's Disease) and "lipid storage diseases" (e.g. Niemann Pick Type C) to test this hypothesis. Specifically, we are assaying the synaptic roles of idnetified genes known to mutate to cause the inherited conditions.
Postdoctoral Positions Available
We are very actively recruiting postdoctoral researchers! We are interested in recruiting cellular and molecular biologists interested in neurobiology, particularly synaptic biology. We are particularly keen to recruit experienced electrophysiologists (patch-clamp, TEVC) and confocal microscopists (live imaging, optogenetics). We are also looking for molecular geneticists with experience in Drosophila or other genetic models (yeast, C. elegans, zebrafish).
We use genetic approaches to study the nervous system, particularly the development, function and plasticity of neuronal synapses. We model many human diseases which involve synaptic dysfunction, including Fragile X syndrome. We use a multidisciplinary approach coupling molecular genetics with neurological techniques including electrophysiology, optical imaging and EM.
If you have an interest, please contact me directly at firstname.lastname@example.org. All inquiries should be accompanied by a CV and statement of specific interests.