The main objective of this project is a study of synaptic plasticity viewed in postischemic neurons and a new mechanisms for ischemic neuronal damage. The principal investigator has recently found that ultrastructure of postsynaptic densities (PSDs) is highly modified following a brief ischemic episode. The structural modification is coordinated with tight anchoring of new signal transduction molecules, substantial alterations of molecular composition and protein phosphorylation in the PSDs. Ischemia is a nonspecific stimulus and it is hypothesized that structural and molecular modification of PSDs following stimulation is a fundamental process of the CNS; i.e., a structural and molecular basis for increased strength of neurotransmission (long term potentiation). However, this process if excessive may amplify the signal pathologically and cause neuronal dysfunction or even neuronal death.
The Specific Aims are: 1. to further study structural and molecular modification of PSDs in postischemic neurons by EM and EM tomography and by biochemical methods; 2. to study time courses of the structural and molecular modification of PSDs using the brains with systemically varied reperfusion and ischemic duration; 3. to study the mechanisms of receptor aggregation. Although glutamate antagonists are neuroprotective in ischemic stroke, they usually cause severe side effects. Understanding structural and molecular modification of PSDs that leads to postischemic enhancement of glutamate transmission may provide a new avenue to protect neuron against stroke. It may also contribute to understanding of fundamental principle of synaptic plasticity.
