The long-term objectives of this project are to (i) identify defects in the subsynaptic cytoskeleton related to the failure of LTP consolidation in rodent models of memory/cognitive impairments and (ii) use this information to develop novel, clinically plausible strategies for counteracting the defects. Work in the PPG led to a model of consolidation involving three classes of membrane receptors that collectively regulate dual actin signaling pathways for assembling and stabilizing actin filaments. Our studies then showed that discrete errors are present in this complex system in three distinctly different rodent models of human conditions associated with memory problems. We also found that one of the releasable modifiers (Brain-Derived Neurotrophic Factor: BDNF) in the LTP model offsets defects in synaptic plasticity when applied directly to brain slices or when upregulated by drugs. The proposed experiments will employ a newly developed method that acutely, facilitates BDNF signaling at synapses, make the critical translational step of moving the analysis of signaling failures and potential therapies to behaving animals, and analyze how signaling defects affect the regional distribution ('maps') of LTP-related synaptic changes during learning.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of California Irvine
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