Activity-Dependent Adaptations of Neuronal Secretory Vesicle Exocytosis

Abstract

Neurons rely on tightly regulated communication systems to maintain stable levels of activity within neural networks. This stability is supported by homeostatic synaptic plasticity, a set of adaptive mechanisms that ensures neurons continue to function reliably even when network activity is altered. While the role of synaptic vesicle–mediated neurotransmitter release in homeostatic plasticity is well established, far less is known about how dense-core vesicle (DCV)–mediated neuromodulator release participates in these adaptive processes. This thesis investigates how two components—DCV exocytosis and the synaptic vesicle protein SV2B—contribute to presynaptic homeostatic regulation in excitatory neurons. It addresses two central questions: (1) how DCV pool dynamics and fusogenicity are regulated during chronic network silencing, and whether DCV exocytosis is required for homeostatic synaptic scaling, and (2) how SV2B supports glutamatergic vesicle function and why its expression is modulated during homeostatic plasticity. DCV’s store neuromodulators that influence neuronal development, excitability, and circuit function. Despite their importance, how DCV’s respond to changes in network activity and whether their exocytosis contributes to homeostatic plasticity has remained largely unclear. In this work, we show that chronic silencing of neuronal activity leads to an accumulation of DCV’s and enhances their release when neurons are reactivated. These changes occur without an increase in DCV protein levels, suggesting that neurons regulate the mobilization and fusogenicity of existing DCV’s rather than upregulation DCV biogenesis. Using a genetic model in which DCV exocytosis is impaired, we further demonstrate that release of DCV cargos is required for the expression of synaptic upscaling. These findings identify DCV mediated neuropeptide release as a potential presynaptic mechanism supporting homeostatic plasticity. In addition, this thesis investigates the function of SV2B, a synaptic vesicle protein whose role in neurotransmission has remained unclear. SV2B is selectively regulated during homeostatic adaptations, suggesting a contribution to stabilizing presynaptic output. We show that neurons lacking SV2B exhibit reduced spontaneous neurotransmission and display abnormalities in vesicle exocytosis and recycling. These results indicate that SV2B is important for maintaining the efficiency and stability of glutamatergic synaptic vesicles, possibly by controlling their trafficking or retrieval during repeated activity. Together, these findings point to two presynaptic pathways that may contribute to maintaining synaptic function during prolonged changes in activity. However, the mechanistic basis through which DCV exocytosis influences homeostatic scaling remains unresolved. Likewise, the precise molecular role of SV2B in preserving vesicle identity and coordinating vesicle recycling during homeostatic adjustments is still not fully defined. By identifying these presynaptic components as candidates in homeostatic regulation, this thesis provides a conceptual and experimental foundation for future work aimed at dissecting causal relationships, determining relevant DCV cargo, and resolving how neuromodulator release and vesicle specialization interface with postsynaptic signalling to maintain stable yet adaptable synaptic function.