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Title: Pharmacological and pathological modulation at presynaptic terminals of small central synapses
Author: Fennell, Kate
ISNI:       0000 0004 7967 3776
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2019
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Many neuropharmacological interventions target presynaptic substrates but the mechanisms of functional modulation at the level of individual terminals are still poorly defined. Addressing this knowledge deficit is fundamental for revealing broader principles of pharmacological action in circuits, and for informing drug research and development. Here, using electrophysiology and genetically-encoded optical reporters of synaptic function - in particular, assays of synaptic vesicle recycling kinetics and transmitter release - we have characterized key mechanisms of modulation in rat hippocampal terminals. Specifically, we demonstrated that the actions of novel synaptic vesicle protein 2A (SV2A) modulators are driven by stimulus intensity and frequency, indicative of a use-dependent mode of action. We also examined the consequences of positive and negative allosteric modulators of metabotropic glutamate receptor 2 (mGluR2) and demonstrated that a concurrent modulation of SV2A and mGluR2 has a synergistic effect, with potentially wide- reaching clinical benefits. In addition, we characterized the role of tau protein in neurotransmission properties and the consequences of expressing pathological tau associated with FTDP-17. We describe the ramifications of FTDP-17 pathology on presynaptic transmission using various models of differential tau expression including tau knockdown and expression of pathological tau carrying the P301L MAPT mutation, Tau(P301L). We show that the presence of Tau(P301L) limits synaptic vesicle recycling pool size and accelerates synaptic vesicle endocytosis but these effects are ameliorated in the presence of Tau(P301L)K18 fibrils, favouring the idea that alterations in synaptic vesicle recycling are largely mediated by pathological tau in its soluble form. Overall, knockdown of tau has a more subtle effect, but also decreases the number of vesicles available for release. Taken together, this data suggests a role of endogenous tau in regulating synaptic vesicle release and retrieval. Neurons expressing Tau(P301L) also exhibit excessive glutamate release, which is again recovered by the addition of Tau(P301L)K18 fibrils. Finally, we show that glutamate clearance in neurons expressing Tau(P301L) is impaired to a similar degree, independent of the presence of Tau(P301L)K18 fibrils. We conclude that it is likely that enhanced glutamate release and slowed reuptake contribute to the synaptotoxicity observed in models of tau pathology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP0364.5 Neural transmission ; RM Therapeutics. Pharmacology