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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048085-05
Application #
7758250
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
2006-02-15
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$268,546
Indirect Cost
Name
Georgetown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Lee, Yeunkum; Lee, Ji Soo; Lee, Kea Joo et al. (2017) Polo-like kinase 2 phosphorylation of amyloid precursor protein regulates activity-dependent amyloidogenic processing. Neuropharmacology 117:387-400
Rozeboom, Aaron M; Queenan, Bridget N; Partridge, John G et al. (2015) Evidence for glycinergic GluN1/GluN3 NMDA receptors in hippocampal metaplasticity. Neurobiol Learn Mem 125:265-73
Lee, Kea Joo; Queenan, Bridget N; Rozeboom, Aaron M et al. (2013) Mossy fiber-CA3 synapses mediate homeostatic plasticity in mature hippocampal neurons. Neuron 77:99-114
Rozeboom, A M; Pak, D T S (2012) Identification and functional characterization of polo-like kinase 2 autoregulatory sites. Neuroscience 202:147-57
Queenan, Bridget N; Lee, Kea Joo; Pak, Daniel T S (2012) Wherefore art thou, homeo(stasis)? Functional diversity in homeostatic synaptic plasticity. Neural Plast 2012:718203
Hoe, Hyang-Sook; Lee, Hey-Kyoung; Pak, Daniel T S (2012) The upside of APP at synapses. CNS Neurosci Ther 18:47-56
Lee, Kea Joo; Lee, Yeunkum; Rozeboom, Aaron et al. (2011) Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory. Neuron 69:957-73
Rogers, Justin T; Rusiana, Ian; Trotter, Justin et al. (2011) Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density. Learn Mem 18:558-64
Lee, Kea Joo; Hoe, Hyang-Sook; Pak, Daniel Ts (2011) Plk2 Raps up Ras to subdue synapses. Small GTPases 2:162-166
Babus, Lenard W; Little, Elizabeth M; Keenoy, Kathleen E et al. (2011) Decreased dendritic spine density and abnormal spine morphology in Fyn knockout mice. Brain Res 1415:96-102

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