1. The organization of AMPA-type glutamate receptors at the synapse.
The best way to study this is with immunogold electron microscopy. There is reason to believe that detailed examination of intra-particle spacing can yield information beyond what is immediately available, related (for example) to the question of whether the receptors are spread out in a uniform manner or instead focus in small clusters. However, this is purely theoretical, and it would require empirical experiments to determine whether the theory is correct.
2. The organization of calcium pumps in neurons.
Calcium is a universal second messenger. To avoid signal “jamming” and toxicity, intracellular [Ca2+] is kept at very low levels, using a variety of transporters and exchangers. A particularly important class is the plasma membrane calcium-dependent ATPases (PMCAs). All four isoforms are found in brain, and each exists as several different splice variants. Some of these splices seem to play an important role in membrane targetting. This project would use immunofluorescence, along with immunogold techniques, to give us a better phenomenological description of this selectivity.
3. Electron tomographic study of the synapse.
We are developing approaches to acquire electron tomographic “stacks” of synaptic profiles at unusually high resolution. It turns out that analysis of these images proves quite difficult, though potentially of great interest. This project would mainly involve image processing and analysis.
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4. Actin regulation in dendritic spine.
Dendritic spines are actin-rich structures; they can change size and shape rapidly, in response to ongoing neuronal activity. For this reason, we have become very interested in regulation of the actin cytoskeleton in spines. A major pathway involves signaling via Rho-family GTPases. Several RhoGEFs (GTP exchange factors) and RhoGAPs (GTPase activating proteins) have been implicated in mental retardation and neuropsychiatric disorders, but very little is known about their organization in brain. This project would involve immunocytochemical localization of one of these molecules.