To understand cognitive function and dysfunction in disease, we use a truly multidisciplinary approach. One approach is to use both traditional and conditional knockout mice to alter specific molecules and then examine subsequent changes in cognitive behavior, synaptic and circuit function, neuronal morphology, and molecules. A complimentary approach is to train animals in learning and memory tasks and measure subsequent biochemical changes in the relevant brain regions. Similarly, we induce lasting synaptic plasticity in hippocampal slices and measure subsequent biochemical changes. Using these approaches and others, we relate molecules, electrophysiology, and behavior with top-down and bottom-up approaches. In many cases, the molecules and genetic mutations we are studying are directly relevant to cognitive disorders such as Autism, Mental Retardation, and Alzheimer’s Disease.
Techniques Used
Bringing together graduate and postgraduate training in acute slice electrophysiology, biochemistry, behavior, and molecular biology, my laboratory uses a variety of technical approaches.
1. Knockout, Knockin, Conditional KO, and inducible KO strategies in mouse models.
2. AAV and HSV viral vectors expressing shRNAi, WT, active, and dominant negative constructs stereotactically injected into specific brain regions of rodents.
3. A multitude of disease relevant behavioral tasks measuring cognitive function including social interaction, learning and memory, ultrasonic vocalizations, mood, anxiety, locomotor activity, working memory, sensorimotor gating, and others.
4. State-of-the art electrophysiology (using Zeiss Axioexaminer microscopes and pClamp software/hardware) including dual, paired whole cell patch recordings of flourescently identified neuronal subtypes in acute brain slices, single cell whole cell recordings (minis, PPF, I/O, resting membrane properties, evoked syanptic responses, etc.) as well as extracellular field recording.
Neuroligins/Neurexins in Cognitive Function/Autism Genetic Model Mice
The transsynaptic cell adhesion molecules known as neuroligins and neurexins have been implicated in human autism. We have recently begun to characterize neuroligin knockout mice as a potential animal model of X-linked mental retardation. Using neuroligin 1, 2, and 3 knockouts,as well as neuroligin 3 point mutation knockin mice and neurexin 1 knockout mice, we have identified profound autism-related behavioral abnormalities. Neuroligins have been implicated in maintaining inhibitory to excitatory synapse ratio and may also play a role in synaptic plasticity. We are now thoroughly characterizing the role of the various neuroligin alleles in both behavioral and electrophysiologic assays. These studies include measures of synaptic plasticity and excitatory to inhibitory synaptic ratio in these mice using both whole cell and extracellular recordings from acute brain slices. We believe these mice represent animal models of autism and provide insights into the future treatment of this enigmatic disorder. Additional genetic animal models of autism are in development.
Presynaptic Proteins and Plasticity in Learning and Memory
My laboratory has begun a systematic effort to understand the role of presynaptic proteins and presynaptic function in learning and memory. Our primary hypothesis is that presynaptic proteins, in particular the active zone protein RIM1a, play a critical role in synaptic plasticity and learning and memory. Extensive preliminary data from my laboratory indicate that RIM1a is critical for normal learning and memory. We are now characterizing the role of RIM1a and presynaptic plasticity at specific synapses in learning and memory. These studies will provide the most direct evidence to date that regulation of presynaptic release machinery is involved in learning and memory.
Glucocorticoid System Modulation of Fear Memory/PTSD
My laboratory has recently discovered that the body?s own natural stress hormone, cortisol, may be useful to treat acquired anxiety disorders such as post-traumatic stress disorder, phobias and other stress-induced neuropsychiatric illnesses. These findings suggest that the release of stress hormones during recall of a fearful memory may be a natural mechanism to decrease the negative emotional aspects of traumatic memory. Treatment with stress hormones is relatively non-specific and may have adverse side effects. Thus, we are now examining the precise molecular mechanisms of corticosterone?s effect in the brain on fearful memories to identify more specific targets for treatment of PTSD, phobia, and other stress-induced neuropsychiatric illness.
Summary and Clinical Relevance
Understanding the molecular basis of cognitive function is critical for a complete understanding of the pathophysiology and potential treatment of neuropsychiatric disorders involving human cognition. These include Autism, schizophrenia, Alzheimer?s disease, learning disability, mental retardation, post-traumatic stress disorder, and cognitive deficits associated with post-traumatic brain injury and major depression. In order to understand complex behavior, my laboratory is examining the molecular basis of cognition at multiple levels.
RESEARCH INTERESTS
Autism: Mechanisms and Future Treatment
Alzheiemer's Disease: Translational Research for Prevention and Treatment
Mental Retardation Syndromes
Molecular Basis of Neuropsychiatric Disease
Molecular Mechanisms of Learning, Memory, & Synaptic Plasticity
RECENT PUBLICATIONS
Tabuchi, K., Blundell, J., Etherton, M.R., Hammer, R.E., Liu, X., Powell, C.M., & Sudhof, T.C., "A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice." Science, 318:71-76, October 2007
Blundell, J., Blaiss, C.A., Etherton, M.R., Espinosa, F., Tabuchi, K., Walz, C., Bolliger, M.F., Sudhof, T.C., & Powell, C.M., "Neuroligin 1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior" Journal of Neuroscience, in press 2010
Zhou, J, Blundell, J, Ogawa, S, Kwon, CH, Zhang, W, Sinton, C, Powell, CM, & Parada, L.F., "Pharmacological Inhibition of mTORC1 Supresses Anatomical, Cellular, and Behavioral Abnormalities in Neural-specific Pten Knockout Mice" Journal of Neuroscience, 29(6):1773-83, 2009
Hawasli, A.H., Benavides, D.R., Nguyen, C., Kansy, J., Hayashi, K., Chambon, P., Greengard, P., Powell, C.M., Cooper, D.C., & Bibb, J.A., "Cyclin-dependent kinase 5 governs learning and synaptic plasticity via regulation of NMDA receptor degradation" Nature Neuroscience, 10 (7):880-886, 2007
Shukla, K., Kim, J., Blundell, J. & Powell, C.M., "Learning-induced GluR1 phosphorylation in the hippocampus resembles that induced by LTP" Journal of Biological Chemistry, 282:18100-18107, 2007
Cai, W., Blundell, J., Han, J., Greene, R.W., Powell, C.M., "Post-reactivation Glucocorticoids Impair Recall of Established Fear Memory." Journal of Neuroscience, 26/37:9560-9566, 2006
Kwon**, C., Luikart**, B.W., Powell**, C.M., Zhou, J., Matheny, S.A., Zhang, W., Li, Y. Baker, S.J., & Parada, L., "Pten Regulates Neuronal Arborization and Social Interaction in Mice." Neuron, 50:377-388, 2006
Powell, C.M., Schoch, S., Monteggia, L., Barrot, M., Matos, M., Sudhof, T.C., & Nestler, E.J., "The Presynaptic Active Zone Matrix Protein RIM1 is Critical for Normal Associative Learning." Neuron, 42:143-153, 2004
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