Spatiotemporal modeling of neuronal protein synthesis in synaptic plasticity

Abstract

Synaptic plasticity, the ability of synapses to undergo changes in their strength, forms the basis for memory formation. Transcription and translation is required to establish such long term changes at synapses. In this thesis, I present results from my studies about how these complex processes are newlineorchestrated to produce diverse cellular responses. We have developed a biochemical model of plasticity-triggered protein synthesis. This model was constrained by reproducing experimental data. We have shown that protein synthesis is high in a narrow range of calcium levels and is gated by BDNF. We found that these properties prevent newlinerunaway activation of the pathway. Despite several positive feedback loops in the model, we have also shown that bistability is unlikely to arise. It is known that different kinds of inputs lead to synthesis of different subsets of mRNA and proteins but the mechanism is unclear. We built a model of key regulatory pathways that control neuronal mRNA synthesis, based on published experimental data. We found that this network newlinedecodes a wide range of temporal stimuli implicated in synaptic plasticity, and generates distinct combinations of mRNA transcripts in response. To explore how this differentially synthesized mRNA is delivered from the nucleus, our model can be incorporated with rate of mRNA transport. We designed an experiment to measure the speed and distance of its transport. We conducted preliminary experiments where we observed BDNF and PKM-zeta mRNA after inducing plasticity in a hippocampal slice, by using fluorescent in situ hybridization (FISH). newlineOur simulation study coupled with experiments provides a framework to study the regulation of differential protein synthesis during transport and at the synapse.