Formation and plasticity of synapses are essential for normal functioning of the brain and key events for learning and adaptive plasticity. Diseases such as addiction, epilepsy, and Alzheimer's that involve maladaptive plasticity appear to highjack these same mechanisms controlling these events leading to disease states. The area of addition is particular pressing given the devastating impact the disease has on society and the clear like between addictive behaviors and the formation of new synapses and/or maladaptive plastic changes in the brain. Therefore, understanding the mechanisms that regulate normal develop and plasticity in the brain are likely to be critical for any advances in treatment of these diseases. The majority of synaptic contacts that form are made on dendritic spines, which are also a key site of synaptic plasticity. Dendritic spines contain specialized structures called postsynaptic densities (PSDs) that are directly apposed to pre-synaptic neurotransmitter release sites and which scale in size with changes in synaptic strength. Despite having understood this relationship for many years, the molecular dynamics of the translocation and accumulation of PSD proteins and presynaptic proteins following structural plasticity remain poorly understood. Our preliminary data indicate that pre- and postsynaptic proteins for scale in a modular fashion with dendritic spine size. We will determine the synaptic molecular architecture and address how the molecular architecture of the spine synapse responds to structural plasticity in three aims: 1) Determine the nanoarchitecture of glutamate receptors at spine synapses. 2) Determine the nanoscale organization of synchronous and asynchronous synaptic release sites. 3) Determine how PSD-95 nanomodule number and plasticity are regulated. Collectively these studies will advance our understand of basic mechanisms that impact the ability of the nervous system to grow and change, events that are likely central to disease of maladaptive plasticity such as addiction and Alzheimer's.
Defects in synaptic structure and function are often associated with developmental disorders and diseases such as addiction, autism, neuropathic pain, and Alzheimer's. By defining basic mechanisms controlling synapse density and NMDAR synaptic localization, our proposed research will promote understanding of the molecular and cellular mechanisms that mediate these events and should provide new insights into the pathology of and potential therapies for disease such as addiction.
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