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RESEARCH ON MEMORY AND SYNAPTIC PLASTICITY
Research on a Powerful Model of Long-Term Memory: Molecular, Electrophysiological, and Behavioral Approaches. Understanding how we remember things for days to weeks and even for a lifetime remains an exciting, unsolved puzzle in neuroscience. If we comprehend the mechanisms underlying formation and storage of memory, we might be able to prevent or treat memory loss. My lab focuses on understanding cellular and molecular mechanisms underlying long-term memory. The brain 'encodes' memory by modifying the neuronal circuitry that underlies a particular behavior. We are interested in knowing what exactly occurs at the cellular and molecular level that leads to alterations in the strength of synapses. We use a model system that is highly advantageous for multi-pronged investigation of memory that lasts for a significant duration of a lifetime: olfactory memory. Long-term olfactory memory formation requires coincident release of glutamate and norepinephrine (NE). We are studying the signaling cascades activated by glutamate and NE and the gene expression pathways that play a critical role in olfactory memory formation.
Research on a Novel Molecular Mechanism of Synaptic Plasticity and Long-Term Memory: Proteolysis through the Ubiquitin-Proteasome Pathway. We are also investigating how protein degradation helps change synaptic strength and store memory. A long-held view of synaptic plasticity has been that short-term synapse modification occurs through phosphorylation of proteins and long-term synapse modification requires gene expression. During my post-doctoral research with Drs. James Schwartz and Eric Kandel at Columbia University, I discovered a role for the ubiquitin-proteasome pathway in long-term memory. Subsequently several other labs corroborated our observations. Now study of the ubiquitin-proteasome pathway in synaptic plasticity has become a trendy area of research. We are studying how protein degradation removes transcription repressors during induction of long-term memory. Because gene expression plays a key role in induction of long-term memory, degradation of the transcription repressors would be a way to determine the threshold for gene induction and the threshold for long-term memory. This research may help explain why we remember only some things for a long time.
Clinical Relevance of Research on Memory and Synaptic Plasticity. In several neurodegenerative diseases such as Alzheimer’s, memory as well as olfaction is impaired early during the development of the disease. Research on olfactory memory is therefore highly likely to shed light on memory deficits that are observed in neurodegenerative diseases. Also, in Alzheimer’s, Parkinson’s and Huntington’s diseases, proteolysis by the ubiquitin-proteasome pathway is impaired. Because synaptic dysfunction is a common defect in these diseases, we are investigating how disruption of proteolysis contributes to synaptic defect and neurodegeneration.
RESEARCH ON ABNORMAL SYNPTIC PLASTICITY AND SYNAPTIC TRANSMISSION
Schizophrenia. Schizophrenia is considered a disorder of the synapse. All the genes implicated in schizophrenia affect the synapse in one way or another. Abnormality of the synapse can cause many symptoms of schizophrenia such as impaired sensory perception. For example, schizophrenics are not able to tell the irrelevant sensory information from the relevant ones. Also, the schizophrenia patients suffer from hallucinations and disorganized thought. A possible neural mechanism of schizophrenia is abnormal synaptic transmission. We have recently developed a project on RGS4, a gene implicated in schizophrenia. We are testing the role of RGS4 in synaptic transmission using a multi-pronged approach. We have identified new splice variants of the RGS4 genes specific to humans. We are studying post-mortem human brain samples for changes in the expression of RGS4 splice variants.
Clinical Relevance of Research on Abnormal Synaptic Transmission. The projects on schizophrenia are likely to explain the mechanisms underlying the disorder. Elucidation of disease mechanisms is critical for identifying potential drug candidates and for therapeutic intervention.
TRAINING ENVIRONMENT FOR STUDENTS AND POST-DOCTORAL FELLOWS
We use sophisticated molecular biological, electrophysiological and behavioral approaches to study major unanswered questions on long-term memory, synaptic plasticity and synaptic transmission. We make use of genomics approaches such as oligonucleotide microarrays in combination with bioinformatics studies of the mouse and human genome. We employ the latest proteomics techniques as well. We use patch-clamp and extracellular recordings for electrophysiological studies. We utilize delivery of small interfering RNA through viral vectors to reduce the expression of specific genes in the brain to relate molecules to behavior. Our research group offers an excellent opportunity to specialize in an experimental approach while benefiting from the wide-ranging expertise available in the laboratory. Moreover, our laboratory offers a genial, collaborative, and supportive atmosphere conducive to learning, the free flow of ideas, enjoyment of research enterprise, and career development.
SELECTED PUBLICATIONS
Dong, C., Upadhya, S.C., Ding, L., Smith, T.K. and Hegde, A. N. (2008). Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation. Learn. Mem. 15: 335-347.
Hegde, A.N. and Upadhya, S. C. (2007). The Ubiquitin-Proteasome Pathway in Health and Disease of the Nervous System. Trends Neurosci. 30: 587-595.
Ding, L., Mychaleckyj, J.C. and Hegde, A. N. (2007). Full length cloning and characterization of splice variants of human and murine genes encoding regulator of G-protein signaling RGS4. Gene 401: 46-60.
Upadhya S.C. and Hegde, A. N. (2007). Role of the Ubiquitin-Proteasome Pathway in Alzheimer’s Disease. BMC Biochemistry 8 (Suppl 1): S12.
Hegde, A. N. and Upadhya SC (2006). Proteasome and transcription: a destroyer goes into construction. BioEssays 28: 235-239.
Upadhya, S. C., Ding, L., Smith, T. K. and Hegde, A. N. (2006). Differential regulation of proteasome activity in the nucleus and the synaptic terminals. Neurochem. Int. 48: 296-305.
Upadhya, S.C. and Hegde, A. N. (2005). Ubiquitin-proteasome pathway components as therapeutic targets for CNS maladies. Curr. Pharm. Design 11: 3807-3828.
Hegde, A. N. (2004). Ubiquitin-Proteasome-Mediated Local Protein Degradation and Synaptic Plasticity. Prog. Neurobiol. 73: 311-357.
Upadhya, S. C., Smith, T. K. and Hegde, A. N. (2004). Ubiquitin-Proteasome-Mediated CREB Repressor Degradation during Induction of Long-Term Facilitation. J. Neurochem. 91: 210-219.
Giustetto, M., Hegde, A. N., Si, K., Casadio, A., Inokuchi, K., Pei, W., Kandel, E. R. and Schwartz, J. H. (2003). Axonal transport of eukaryotic translation elongation factor 1 alpha mRNA couples transcription in the nucleus to long-term facilitation at the synapse. Proc. Natl. Acad. Sci. USA 100: 13680-13685.
Upadhya, S. C. and Hegde, A. N. (2003). A potential proteasome-interacting motif within the ubiquitin-like domain of parkin and other proteins. Trends Biochem Sci. 28: 280-283.
Hegde, A. N. (2003). MHC Molecules in the vomeronasal organ: contributors to pheromonal discrimination? Trends Neurosci. 26: 646-650.
Hegde, A. N. and DiAntonio A (2002). Ubiquitin and the synapse. Nature. Rev. Neurosci. 3: 854-861.
Hegde, A. N., Inokuchi, K., Pei, W., Casadio, A., Ghirardi, M., Chain, D. G., Martin K. C., Kandel, E. R. and Schwartz, J. H. (1997). Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 89: 115-126.
SELECTED BOOK CHAPTERS
Hegde, A. N. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity. New Encyclopedia of Neuroscience, Albright, T.D., Bloom, F.E., Gage, F.H., Spitzer, N. C. and Squire, L.R. (Eds). Elsevier: New York (In Press).
Hegde, A. N. Proteolysis and Synaptic Plasticity. Learning and Memory: A Comprehensive Reference, Byrne, J.H., Eichenbaum, H., Menzel, R., Roediger, H. and Sweatt, J.D. (Eds). Elsevier: New York (In Press).
E-mail: ahegde@wfubmc.edu
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