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Office:
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ND4.502A |
214-645-6251/ 214-645-6240(FAX),
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Lab:
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ND4.504 |
214-645-6202
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Opportunities:
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Actively seeking interested Postdoctoral Fellows and Graduate Students
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My laboratory is focused on the molecular and cellular mechanisms of cognitive function and cognitive dysfunction in disease. In our basic research on learning and memory, we are interested in how molecular and cellular alterations lead to behavioral changes that last for the better part of a lifetime in response to relatively brief environmental stimuli.
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.
Neuroligins/Neurexins in Cognitive Function—Autism Genetic Model Mice
The transsynaptic cell adhesion molecules known as neuroligins have been implicated in human X-linked mental retardation with and without autistic features. We have recently begun to characterize neuroligin knockout mice as a potential animal model of X-linked mental retardation. Using neuroligin 1 and 2 double knockouts, we have identified profound deficits in learning and memory including social learning, emotional learning, and spatial learning. Neuroligins have been implicated in maintaining inhibitory to excitatory synapse ratio and may also play a role in synaptic plasticity. We now plan to thoroughly characterize the role of the various neuroligin alleles in learning and memory and other behaviors. We will also further examine synaptic plasticity and excitatory to inhibitory synaptic ratio in these mice with the help of collaborators. We believe these mice may represent animal models of X-linked mental retardation and provide insights into the future treatment of this disorder.
Presynaptic Proteins and Plasticity in Learning and Memory
Recent genetic studies of learning and memory have made significant progress in identifying postsynaptic mechanisms involved in learning and memory. Relatively little effort has been aimed at elucidating the role of presynaptic proteins and presynaptic plasticity in mammalian 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. RIM1a knockout (RIM1a-/-) mice have deficits in learning and memory. Additional preliminary data indicate that RIM1a is phosphorylated at its major protein kinase A (PKA) site in the hippocampus during learning and that this phosphorylation is specific to associative learning.
My laboratory will now further characterize the role of RIM1a and its regulation by PKA in both synaptic plasticity and learning and memory. Also, we will conditionally delete RIM1a from specific synapses and examine the effect on 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. Specifically, we used an animal model to demonstrate that the injection of corticosterone, the animal equivalent of cortisol, after recalling a traumatic memory decreases the fearful nature of the memory in a lasting way. This treatment does not erase the initial traumatic memory, but rather augments a competing memory that decreases the fearful response to the initial memory (known as extinction memory). 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.
Conversely, patients with post-traumatic stress disorder (PTSD) have blunted stress hormone responses and thus, may not decrease fearful memories normally over time. It is thought that this abnormal persistence of traumatic memory is responsible for PTSD symptoms. This suggests that patients with post-traumatic stress disorder may be treated by pairing reactivation of their fearful memories during therapy with stress hormone treatment. 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
Neurons in the central nervous system are complex machines designed to accept a rich diversity of inputs and alter their responses in meaningful and lasting ways. The molecular signal transduction events that translate certain input patterns into lasting alterations of neuronal function are beginning to be elucidated. How these molecular and cellular alterations conspire to alter behavior in a lasting fashion in response to external cues remains largely a mystery. Understanding this complex interplay between molecules, neuronal function, and behavior is the focus of my laboratory
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.
Recent Publications (updated June 2009):
Hawasli, A.H., Koovakkattu, D., Hayashi, K., Anderson, A.E., Powell, C.M., Sinton, C.M., Bibb, J.A., Cooper, D.C. (2009) Regulation of Hippocampal and Behavioral Excitability by Cyclin-Dependent Kinase 5 PLoS One (in press).
Zhou, J, Blundell, J, Ogawa, S, Kwon, CH, Zhang, W, Sinton, C, Powell, CM, & Parada, L.F. (2009) Pharmacological Inhibition of mTORC1 Supresses Anatomical, Cellular, and Behavioral Abnormalities in Neural-specific Pten Knockout Mice. Journal of Neuroscience, 29(6):1773-83.
Suris, A., North, C., Powell, C.M., Adinoff, B., Greene, R. (2009) Effects of Exogenous Glucocorticoid on Combat-related PTSD Symptoms. Annals of Clinical Psychiatry (in press).
Blundell, J., Tabuchi, K., Bolliger, M.F., Blaiss, C.A., Brose, N., Liu, X., Sudhof, T.C., & Powell, C.M. Increased Anxiety-like Behavior in Mice Lacking the Inhibitory Synapse Cell Adhesion Molecule Neuroligin 2. (2008) Genes Brain & Behavior, Epub ahead of print (in press).
Kaeser, P., Kwon, H., Blundell, J., Chevaleyre, V., Morishita, W., Malenka, R.C., Powell, C.M., Castillo, P.E., & Sudhof, T.C. (2008) RIM1a phosphorylation at serine-413 by protein kinase A is not required for presynaptic long-term potentiation or learning. PNAS, 105(38), 14680-5.
Blundell, J., Kouser, M., & Powell, C.M. (2008) Systemic Inhibition of Mammalian Target of Rapamycin Inhibits Fear Memory Reconsolidation. Neurobiology of Learning and Memory, 90, 28-35.
Tabuchi, K., Blundell, J., Etherton, M.R., Hammer, R.E., Liu, X., Powell, C.M., & Sudhof, T.C. (2007) A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice. Science, 318, 71-76.
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. (2007) Cyclin-dependent kinase 5 governs learning and synaptic plasticity via regulation of NMDA receptor degradation. Nature Neuroscience, 10(7):880-6.
Shukla, K., Kim, J., Blundell, J. & Powell, C.M. (2007) Learning-induced GluR1 phosphorylation in the hippocampus resembles that induced by LTP. Journal of Biological Chemistry, 282, 18100-18107.
Cai, W., Blundell, J., Han, J., Greene, R.W., Powell, C.M. (2006) Post-reactivation Glucocorticoids Impair Recall of Established Fear Memory. J. Neuroscience 26(37), 9560-9566.
Powell, C.M. & Miyakawa, T. (2006) Schizophrenia-relevant Behavioral Testing in Rodent Models: A Uniquely Human Disorder? Biological Psychiatry 59, 1198-1207.
Kwon**, C., Luikart**, B.W., Powell**, C.M., Zhou, J., Matheny, S.A., Zhang, W., Li, Y. Baker, S.J., & Parada, L. (2006) Pten Regulates Neuronal Arborization and Social Interaction in Mice. Neuron 50, 377-388. **Equal Contribution
Powell, C.M. (2006) Gene Targeting of Presynaptic Proteins in Synaptic Plasticity and Memory: Across the Great Divide. Neurobiology of Learning and Memory 85, 2-15.
Powell, C.M., Schoch, S., Monteggia, L., Barrot, M., Matos, M., Sudhof, T.C., & Nestler, E.J. (2004) The Presynaptic Active Zone Matrix Protein RIM1a is Critical for Normal Associative Learning. Neuron 42, 143-153.
Monteggia, L.M., Barrot, M., Powell, C.M., Berton, O., Galanis, V., Gemelli, T., Meuth, S., Nagy, A., Greene, R.W., Nestler, E.J. (2004) Essential Role of Brain Derived Neurotrophic Factor in Adult Hippocampal Function. PNAS 101, 10827-10832.
Torabi, A.M., Mendelsohn, D., Powell, C.M. (2004) Multilevel Intramedullary Spinal Neurocysticercosis with Eosinophilic Meningitis. Archives of Neurology 61 (5), 770-772.
