My laboratory is focused on the molecular and cellular mechanisms of cognition with an emphasis 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 elucidate the molecular basis of learning and memory, 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 learning and memory behavior as well as synaptic plasticity. 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.
Neuroligin-based Models of Autism and Mental Retardation
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 and autism. 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 are now characterizing the role of the various neuroligin alleles in autism and mental retardation-related behaviors. We are also examining synaptic plasticity and excitatory to inhibitory synaptic ratio in these mice with the help of collaborators. We believe these mice represent accurate animal models of idiopathic autism with or without mental retardation and may provide insights into the future treatment of these disorders.
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 RIM1α, play a critical role in synaptic plasticity and learning and memory. Using a variety of cre driver lines, we will use conditional deletion of RIM1α to understand the role of presynaptic plasticity at particular synapses in learning and memory. Extensive preliminary data from my laboratory indicate that RIM1α is critical for normal learning and memory. RIM1α knockout (RIM1α-/-) mice have deficits in learning and memory. Additional preliminary data indicate that RIM1α 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 RIM1α and its regulation by PKA in both synaptic plasticity and learning and memory. Specifically, we are investigating the role of RIM1α in long-term synaptic plasticity in area CA1 of the hippocampus. We are further characterizing the phosphorylation of RIM1α during learning and synaptic plasticity. Finally, we will directly test the hypothesis that phosphorylation of RIM1α at its primary PKA site is required for normal learning and memory using knockin mice with a point mutation at the PKA site. These studies will provide the most direct evidence to date that regulation of presynaptic release machinery is involved in learning and memory.
Schizophrenia Related Behaviors and Presynaptic Proteins
Schizophrenia is a complex psychiatric disorder of cognitive function. Alterations in glutamatergic synaptic function have been implicated in schizophrenia. Hypofunction of glutamatergic synapses can occur via alterations in either pre or postsynaptic molecules. In fact, a variety of presynaptic proteins are decreased in the brains of human schizophrenics. My laboratory has established a battery of schizophrenia-related behaviors to test the hypothesis that global alterations in presynaptic proteins can lead to schizophrenia-related behavioral abnormalities. This battery includes tests of sensorimotor gating (prepulse inhibition), locomotor responses to novelty, responsiveness to the psychotomimetic drugs MK-801 and amphetamine, and social interactions. Soon tests of working memory, attention, and impulsivity will be included. Using these behaviors, we have generated substantial preliminary data indicating that RIM1α-/- mice exhibit multiple schizophrenia related behavioral abnormalities, while mutants of RIM1α binding partners synaptotagmin 1 and Rab3A do not exhibit these abnormalities. An ongoing collaboration with Dr. Carol Tamminga will allow us to directly measure RIM1?? levels in human schizophrenic brains. This work has been funded by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD). Additional collaborations with UTSW and outside investigators to examine relevance of various proteins in schizophrenia-relevant behavioral abnormalities are ongoing.
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 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.
Selected Recent Publications:
Blundell, J., Kouser, M., & Powell, C.M. (2008) Systemic Inhibition of Mammalian Target of Rapamycin Inhibits Fear Memory Reconsolidation. Neurobiology of Learning and Memory, in press.
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.
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., Schoch, S., Monteggia, L., Barrot, M., Matos, M., Sudhof, T.C., & Nestler, E.J. (2004) The Presynaptic Active Zone Matrix Protein RIM1?? is Critical for Normal Associative Learning. Neuron 42, 143-153.
RESEARCH INTERESTS
Molecular Mechanisms of Learning and Memory
Molecular Mechanisms of Synaptic Plasticity
Molecular Basis of Neuropsychiatric Disease
Autism Genetic Mouse Models
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
SIGNIFICANT PUBLICATIONS
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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