Pannexin-1-Dependent Long-Term Depression at the CA3-CA1 Synapse
Date
2021-04-09
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Abstract
Long-term depression (LTD) is a form of synaptic plasticity characterized as a long-lasting decrease in synaptic strength. It is a critical mechanism underlying learning and memory. The most commonly studied form of LTD depends on the activation of the postsynaptic glutamate receptor, NMDA receptor (NMDAR), within the hippocampus. Classically, LTD is thought to result from the influx of ions (particularly calcium, Ca2+) through the NMDAR. However, this classical model has come into question as evidence supporting non-ionotropic NMDAR signaling (i.e. “metabotropic signaling”) during LTD has increased over the past few years. Previous work in the Thompson lab has linked metabotropic NMDAR signaling to the large pore channel, Pannexin-1 (Panx1) under pathological conditions through Sarcoma (Src) kinase activation. Recently, Panx1 has been implicated in synaptic plasticity, particularly hippocampal LTD. Therefore, my overarching hypothesis for this thesis is that Panx1 acts as a downstream target of non-ionotropic NMDAR signaling during hippocampal LTD. Here I demonstrate that all components of the NMDAR-Src-Panx1 pathway are necessary for successful hippocampal LTD within the CA3-CA1 synapse following a low-frequency stimulation (LFS) of 3 Hz. Additionally, I show that Src interaction with Panx1’s C-terminal domain (CTD) is required for successful synaptic depression. Together, this supports a role for metabotropic NMDAR activation of Panx1 via Src kinase during LFS-induced LTD. Towards the end of this thesis, I begin to hypothesize and study the potential roles and contributions of Panx1 during LTD. Although still preliminary, my data suggests ATP release through Panx1 and the activation of nearby purinergic receptors, particularly P2X4 receptors (P2X4Rs), may be critical drivers of LTD downstream of NMDAR activation.
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Keywords
Plasticity, LTD, Pannexin-1, NMDARs
Citation
Werner, A. C. (2021). Pannexin-1-Dependent Long-Term Depression at the CA3-CA1 Synapse (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.