Synaptic Function in the Nematode C. Elegans

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: ERIK M JORGENSEN
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $323,587
Funding agency: National Institute of Neurological Disorders and Stroke

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- µ2.
 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.

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