Communication between nerve cells takes place by the release of neurotransmitters at synapses. Signaling can be extremely rapid ? transmitting information via hundreds of action potentials per second. It is not possible to synthesize new synaptic vesicles at this pace, so rapid recycling is essential. Although endocytosis at the synapse is at the core of synaptic transmission, the debate about the mechanism has continued for over 40 years without resolution. We recently discovered that synaptic vesicle endocytosis at synapses in the nematode C. elegans and mouse hippocampal neurons occurs as rapidly as 30-50 ms rather than 30 seconds, as determined previously. Our preliminary results suggest that this process requires synaptotagmin and interacting adaptors.
Aim 1. Synaptotagmin. We will determine if ultrafast endocytosis and vesicle budding is defective in the absence of synaptotagmin in C. elegans.
Aim 2. Adaptors. Synaptotagmin interacts with two mu-homology domain proteins: stonin and AP2- 2. We will determine if ultrafast endocytosis is defective in stonin mutants and vesicle regeneration is defective in AP2 mutants. We will also determine whether these proteins are localized to endocytic domains at the synapse.
Aim 3. Cargo. We will determine if synaptic vesicle components synaptotagmin and synaptobrevin are enriched at endocytic sites before stimulation and whether they are recovered by ultrafast endocytosis in rat hippocampal neuron cultures. There is growing evidence that understanding synaptic vesicle endocytosis will have direct impact on applied health research, since mutations in endocytosis play causative roles in Parkinson's Disease and contribute to Alzheimer's Disease. It is our hope that understanding the process of endocytosis may lead to drug therapies for these diseases in the future. Finally, we are developing innovative new techniques that will aid other researchers by bringing new weapons to bear on these and other problems.
Nerve cells communicate via synaptic transmission, but defects in this process can lead to diseases of the nervous system, such as Parkinson's Disease and Alzheimer's Disease. By studying the basic processes of recycling at neuronal synapses, we hope to understand the causes of neurodegenerative diseases as well as develop novel therapies.
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