Calcium/calmodulin dependent kinase II (CaMKII) is widely expressed and activation of CaMKII plays a fundamental role in several cellular processes ranging from proper cell division and carbohydrate metabolism to synaptic plasticity and learning and memory (see Lisman et al., 2002 and Colomer and Means, 2007). The long-term goal of this research is to investigate the role of novel phenomenon called locally-induced propagating synaptic (L-IPS) translocation of calcium/calmodulin kinase II (CaMKII). This heterosynaptic process can be described as a slow, wave-like propagation of synaptic CaMKII accumulation that stems from localized application of glutamate and glycine to a small portion of dendrite, activating a subset of contiguous synapses. Within 10 minutes after this stimulation, CaMKII accumulates at synapses not only at the stimulation site but at synapses throughout the dendritic arbor. This process relies on NMDA receptor activation, L-type Ca2+ channels and results in an increase of expression of the AMPA-type glutamate receptor subunit GluR1 at synapses (~18% above baseline).
Specific aims i nclude: determining if heterosynaptic plasticity induced by synaptic accumulation following L-IPS translocation occludes long-term potentiation (LTP;a well-characterized proposed mechanism of synaptic plasticity). As well, investigation into expression levels of other synaptic proteins (e.g., GluR2, and NMDA receptor subunits) following L-IPS translocation of CaMKII will be conducted. The current research proposes studies to confirm stability and reversibility of synaptic CaMKII accumulation resulting from L-IPS translocation. Finally, changes in spine morphology will also be examined both during and at periods after L-IPS translocation of CaMKII. Live-cell imaging of reporter constructs expressed in dissociated hippocampal cell culture will be the predominate method employed to investigate these questions addressing the neuronal function of L-IPS translocation of CaMKII. The finding that local stimulation of a small dendrite area results in synaptic accumulation of CaMKII at non-stimulated synapses throughout the dendritic arbor alludes to a novel property of plasticity and intracellular signaling;thus, functional characterization of this process needs to be conducted. Several diseases implicate a role for CaMKII including Alzheimer's disease, epilepsy, Parkinson's disease and cell loss due to ischemia. Uncovering the role of this heterosynaptic phenomenon could elucidate further the dynamics of cell-wide CaMKII activation and provide possible avenues of discovery into the mechanisms of some of these disorders.
Calcium/calmodulin dependent kinase II (CaMKII) migrates to synapses throughout a neuron following stimulation of a small segment of dendrite. This locally-induced propagating synaptic (L-IPS) translocation of CaMKII requires further functional characterization to determine its role in neuron function. As CaMKII activation is involved in several physiological processes, ranging from myocardial contraction to synaptic plasticity, as well as neurological disorders like Alzheimer's, epilepsy and cell death due to stroke/ischemia, it is of interest to uncover why CaMKII signals activity from one local site to all the synapses of a neuron.
