Molecular mechanisms of synapse loss

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DESCRIPTION (provided by applicant): The proper development of neuronal connections depends on precisely controlling the balance between formation and elimination of synapses. These opposing processes also play important roles in synaptic plasticity, learning and memory. Compared to the current wealth of data regarding synaptogenesis, however, relatively little is known about the molecular events underlying the loss of central synapses. We have recently identified a novel mechanism of synapse loss centered on the serum-inducible kinase (SNK), a serine-threonine protein kinase of the polo family. In cortex and hippocampus, the short-lived SNK is induced by synaptic activity and subsequently promotes loss of excitatory synapses and dendritic spines (the primary loci of excitatory synapses in the CMS). SNK exerts its effect on synapses via the phosphorylation- and ubiquitin-dependent degradation of specific postsynaptic substrates such as SPAR, an important morphogen for dendritic spines. Because SNK regulates the number, structure and composition of synapses and spines, this kinase is likely to be important for shaping the long-term functional properties of neurons. We have identified an additional potential substrate of SNK, the abundant postsynaptic Ras regulator SynGAP. Ras signaling is of critical importance for a wide variety of neurobiological processes including synaptic plasticity, development, and protection from excitotoxic insults. Biochemical and molecular approaches will be employed in Aim 1 to determine whether SynGAP and SNK physically interact and whether SynGAP is a direct phosphorylation substrate of SNK. In Aim 2 we will analyze the functional relationship between SNK and SynGAP in vitro and determine whether SNK regulates SynGAP and Ras in neurons. Finally, the role of a putative SNK/SynGAP/Ras regulatory network in regulating dendritic spine morphology will be addressed in Aim 3. The experiments described in this proposal are essential for understanding the mechanisms of SNK action and may have broad impact in the fields of synaptic plasticity, synapse development, and pathological synapse loss. Elucidating these pathways is likely to be of clinical significance and highly relevant to public health in view of the fact that neocortical synapse loss is a hallmark of human neurodegeneration and is the major correlate of cognitive decline in many forms of dementia.