The brain was once thought of as a static organ, reaching development before or shortly after birth. Based on evidence of growth and adaptation, this notion has been replaced and it is now believed the brain demonstrates a high degree of plasticity. Despite these advances in understanding of how the brain changes with learning and experience, the mechanisms underlying this plasticity are not completely understood. It is generally accepted that changes in neuronal morphology and neurotransmitter receptor expression at the cell surface contribute to adaptation. These mechanisms are often activity-dependent and so this project addresses the question of how alterations in neuronal activity are translated through signaling mechanisms to changes in dendritic spines and cell surface receptor expression. This project involves the study of several proteins which may link changes in synaptic activity to functional changes involving receptor surface expression. This proposal focuses on two of these proteins: Serum inducible kinase (SNK) and N-ethylmaleimide sensitive factor (NSF).
The specific aims for this application are to 1) demonstrate endogenous SNK and NSF interact in neurons, 2) determine the influence of SNK binding NSF on NSF interaction with the AMPA receptor subunit, GluR2 and 3) examine if SNK-NSF interaction disrupts stability of AMPA receptors at the cell surface. This research will provide further understanding of mechanisms contributing to changes in synaptic activity. This knowledge will lead to greater understanding of synaptic plasticity and reveal processes underlying learning. In view of the fact that SNK has been shown to promote synapse loss and NSF is reported to be involved in epilepsy, these results will provide insight into epileptogenic pathways and mechanisms leading to cell death as occurs with excitotoxicity and neurodegeration disorders, such as Alzheimer's Disease (AD). ? ? ?
| Evers, Danielle M; Matta, Jose A; Hoe, Hyang-Sook et al. (2010) Plk2 attachment to NSF induces homeostatic removal of GluA2 during chronic overexcitation. Nat Neurosci 13:1199-207 |
