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Functional conservation of the AKT kinase action on the synaptic vesicle release machinery between Drosophila and rat

Leung, Yeung-Yeung

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Abstract

Spontaneous vesicle release has long been dismissed as a stochastic byproduct of vesicle release machinery to achieve high fidelity evoked release. Nevertheless, studies of the decade have identified its important role in the development and function of synapses. Interestingly, spontaneous neurotransmitter release appears to be regulated differently at individual vesicle release sites, but how this dynamic regulation is achieved is largely unclear. Our earlier study at the Drosophila neuromuscular junction (NMJ) has revealed a novel synaptic function of the ubiquitous kinase AKT in regulating spontaneous vesicle release. Since AKT has been repeatedly reported as a risk gene for several neurological disorders, the potential conservation of this pathway in the mammalian central nervous system might implicate an intriguing new mechanism for human diseases. This study revealed that the AKT regulation of spontaneous vesicle release is conserved in the hippocampal cultured neuron. Suppressed AKT activity induced a greater degree of enhancement in excitatory over inhibitory spontaneous neurotransmitter release, and elicited oscillatory bursting activity in hippocampal neurons. Both of which closely link to the etiology of Schizophrenia and Autism Spectrum Disorders. Since acute AKT inhibition suppressed high frequency triggered evoked vesicle release at both hippocampal synapses and Drosophila NMJ, this data suggested that AKT might function in dynamically regulating the clamping status of vesicle release machinery, which may offer a well-fitting mechanism for how release sites exhibit a spectrum of preference for evoke/spontaneous vesicle release. Intriguingly, recombinant adeno-associated virus (rAAV)-shRNA mediated knockdown of the ubiquitously expressed AKT isoform, AKT1, reduced the rate of spontaneous vesicle release, whereas silencing the predominantly brain expressed AKT3 resulted in elevation. Since compensatory expressions of the two isoforms were observed, understanding how the interplay between the AKT isoforms leads to the differential outcome may provide provocative clues in disease etiology. The second part of this thesis presents the experimental data that contributed in a collaborative project to construct a highly realistic three-dimensional mathematical model of calcium dynamics in Drosophila NMJ boutons. Our experimental data show a linear relationship between bouton surface to volume ratio and stimulation induced peak calcium rise. Compared to bigger size type 1b bouton, the smaller size type 1s bouton elicited more robust upsurge in peak calcium at lower stimulation frequency and exhibited faster rise kinetics at all stimulation frequency within the physiology range. Nevertheless, the variation of calcium dynamics of the two bouton types seems not fully explainable by size, isolation of the critical parameters would require detailed computational analysis.

Item Type: Dissertation
Supervisor: Schuster, Prof. Dr. Christoph
Date of thesis defense: 18 April 2016
Date Deposited: 27 Apr 2016 08:37
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
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