The ability of neurons within the hippocampus to differentially respond to specific temporal and spatial patterns of stimulation underlies the storage of memory and information in neural circuits. Signal transduction pathways are critical for information storage, and alterations in key signaling molecules, such as the cAMP-dependent protein kinase (PKA) signaling pathway, modify both hippocampus-dependent learning and a form of synaptic plasticity known as long-term potentiation (L-LTP). Alterations in these signaling pathways play a critical role in neurological and psychiatric disorders such as alcoholism, depression, schizophrenia and Alzheimer's disease. Despite this clinical relevance, little is known about how signaling pathways respond differentially to distinct temporal and spatial patterns of synaptic input. The dynamics of PKA localization to subcellular compartments by A-Kinase Anchoring Proteins (AKAPs) provides a potential mechanism for such spatial and temporal specificity. We propose an innovative and transformative set of experiments to investigate the critical role of multi-protein complexes involving PKA and AKAPs in neuronal information storage and synaptic plasticity.
SPECIFIC AIM 1. Define the role of protein kinase A (PKA) in the temporal sensitivity of late phase long-term potentiation (L-LTP). Fluorescent imaging, electrophysiology, biochemistry and computational modeling will be utilized to measure the level of cAMP and PKA activity after LTP inducing stimuli. These integrated experiments and modeling will evaluate the role of NMDA and D1 receptor signaling in long-lasting forms of synaptic plasticity, and will evaluate the temporal sensitivity of interactions between signaling pathways activated by these receptors.
SPECIFIC AIM 2. Define the spatial specificity of biochemical signaling mechanisms underlying L-LTP induction in hippocampal neurons. Computational modeling, fluorescent imaging and electrophysiology approaches will be utilized to measure L-LTP and gradients of cAMP and PKA activity in the presence or absence of inhibitors of PKA anchoring. Successful completion of the research will form the basis for investigating how alterations in this pathway contributes to psychiatric disease such as schizophrenia and alcoholism. ? ?
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