This project focuses on the role of signal transduction mechanisms in hippocampal Long-term Potentiation (LTP) and memory formation. In the most recent Project Period we have been exploring the role of the Mitogen-Activated Protein Kinase (MAPK) family of signal transduction cascades in hippocampal synaptic plasticity and learning, focusing on the mechanisms through which this pathway controls memory-associated gene transcription. We initiated our studies in this area about 15 years ago by determining that the Extracellular-Signal Regulated Kinase (ERK) isoforms of MAPK are necessary for NMDA receptor-dependent LTP in area CA1. We then transitioned to studies in the behaving animal and discovered that ERK is activated in the hippocampus with contextual associative conditioning, and that ERK activation is necessary for fear conditioning and for spatial learning in the Morris water maze. Studies from a wide variety of laboratories have now shown that MAPK signaling is involved in many forms of synaptic plasticity and learning, in essentially every species that has so far been examined including humans. Given the clear importance of understanding the roles and regulation of ERK in synaptic plasticity and learning, for the next Project Period we propose to continue our investigations into the genomic and epigenomic targets of ERK in the hippocampus. We will pursue the following three Specific Aims: 1: To test the hypothesis that the ERK/MSK pathway regulates histone methylation in the hippocampus. 2: To test the hypothesis that alterations in hippocampal histone methylation occur with memory formation and are necessary for long-term memory and LTP. 3: To test the hypothesis that inhibition of histone de-methylation augments memory formation. By focusing on this important new target for the ERK pathway in hippocampus, histone methylation, we will continue to formulate a comprehensive model of ERK involvement in molecular decision-making in synaptic plasticity and memory.
The discoveries potentially arising from this Project will be broadly relevant, encompassing mechanisms related to psychiatric disorders, aging, drug addiction, cognition, memory, and learning disabilities.
One Aim of the Project specifically involves preclinical studies to evaluate a potential new type of treatment for learning and memory disorders.
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|Zovkic, Iva B; Paulukaitis, Brynna S; Day, Jeremy J et al. (2014) Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature 515:582-6|
|Almonte, Antoine G; Qadri, Laura H; Sultan, Faraz A et al. (2013) Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity. J Neurochem 124:109-22|
|Zovkic, Iva B; Sweatt, J David (2013) Epigenetic mechanisms in learned fear: implications for PTSD. Neuropsychopharmacology 38:77-93|
|Sweatt, J David (2013) Pitt-Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Exp Mol Med 45:e21|
|Zovkic, Iva B; Guzman-Karlsson, Mikael C; Sweatt, J David (2013) Epigenetic regulation of memory formation and maintenance. Learn Mem 20:61-74|
|Rahn, Elizabeth J; Guzman-Karlsson, Mikael C; David Sweatt, J (2013) Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory. Neurobiol Learn Mem 105:133-50|
|Sweatt, J David (2013) The emerging field of neuroepigenetics. Neuron 80:624-32|
|Lithner, Christina Unger; Lacor, Pascale N; Zhao, Wei-Qin et al. (2013) Disruption of neocortical histone H3 homeostasis by soluble A?: implications for Alzheimer's disease. Neurobiol Aging 34:2081-90|
|Day, Jeremy J; Childs, Daniel; Guzman-Karlsson, Mikael C et al. (2013) DNA methylation regulates associative reward learning. Nat Neurosci 16:1445-52|
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