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.