DEFINING THE ROLE OF CAMKII IN SYNAPTIC PLASTICITY

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A promising and widely studied example of vertebrate synaptic plasticity is long-term potentiation (LTP), the persistent synaptic enhancement seen following a brief period of coincident pre- and postsynaptic activity. It has been suggested that the cellular and molecular mechanisms responsible for LTP will elucidate physiological and pathological phenomena including learning, memory, developmental synapse specificity, pain, neuronal death, epilepsy and dementia. The cellular signaling responsible for generating LTP has been studied extensively. Previous studies indicate that calcium/calmodulin-dependent protein kinase II (CaMKII) is both necessary and sufficient to produce LTP and thus may mediate the formation of memories. Here we will examine cellular and molecular consequences of increased CaMKII activity that may contribute to LTP. The central hypothesis to be tested is that increased postsynaptic CaMKII activity increases the number of AMPA receptors at excitatory synapses: both at synapses containing and not containing AMPA receptors. This will be examined with several complementing methodologies including electrophysiology, two photon imaging of GFP-tagged receptors, and immunohistochemistry with light and electron microscopy. These studies will use rodent hippocampal slices (acute and organotypic) and dissociated cultured neurons. A primary motivation to understand the cellular signaling responsible for learning and memory is to understand and alleviate diseases affecting these functions. Toward this goal, we will examine LTP and the role of CaMKII in transgenic mice expressing mutant PS-1, a protein strongly linked to Alzheimer's disease. This protein perturbs calcium homeostasis and our preliminary data show these mice have abnormally large LTP. SA1: To determine the mechanism(s) by which CaMKII increases synaptic AMPA-receptor function. SA2: To determine if CaMKII converts silent synapses into functioning synapses. SA3: To determine if dendritic exocytosis plays a role in LTP. SA4: To determine if LTP is enhanced in mice expressing FAD mutant presenilin-1.