Thursday, November 21, 2024
11/21/2024
The homeostatic plasticity allows neural circuits to restore baseline function by rebalancing pre- or post- synaptic function. Impaired homeostatic responses underlie the pathophysiology of a variety of neurological and psychiatric diseases. The core principle of homeostatic plasticity is that synaptic strength is scaled up or down proportionally to the degree of neural disturbance. Without this synaptic scaling, information flow can be lost or distorted. One of the key factors that regulate neurotransmitter release and thus synaptic strength is the abundance of voltage-gated CaV2 calcium channels at the presynaptic terminal. To elucidate the relationship between CaV2/UNC-2 channel abundance and neurotransmitter release, we used the nematode C. elegans, a simple genetic model organism that possesses highly conserved CaV2 channels and active zone proteins. Using CRISPR/Cas9, we endogenously tagged CaV2/UNC-2 channels with GFP and introduced either a gain- or loss-of-function mutation. When we compared wild-type and UNC-2 mutant forms, we found that channel function inversely correlates with their abundance. However, our preliminary data showed that synaptic vesicle (SV) exocytosis, but not channel function itself, dictates UNC-2 abundance. Loss of UNC-13 function, which causes an SV exocytosis defect, increases channel abundance. In contrast, an open syntaxin mutation, which enhances SV exocytosis by bypassing SV priming, decreases channel abundance. Based on these findings, we hypothesize that a high rate of neurotransmitter release negatively regulates CV2/UNC-2 channel levels. This negative feedback regulatory mechanism provides presynaptic neurons with the ability to scale up or down neurotransmitter release by adjusting CaV2 channel levels independently of postsynaptic inputs. To further validate our hypothesis, we will employ a wide array of SV exocytosis mutations alongside optogenetic and chemical genetic tools to delve deeper into the mechanisms controlling presynaptic UNC-2 levels. Concurrently, we aim to identify the core active zone proteins crucial for activity-dependent UNC-2 abundance modulation. Completion of the project will validate a previously unidentified form of presynaptic homeostatic plasticity that operates independently of post-synaptic inputs.
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