How the presynapse shapes its molecular composition in an energetically optimal manner

Understanding how neurons regulate their protein composition to refine synaptic connections across millimeters of space provides critical insights into the mechanisms of synaptic plasticity. The discovery of local protein synthesis in subcellular compartments has shown how neuronal activity can locally meet the metabolic demands of synaptic plasticity$^{1,2}$. Despite the experimental challenges posed by the long and complex branches of axons, the presence of mRNA and local protein synthesis in presynaptic boutons has been clearly demonstrated$^{3,5}$. In this study, we developed an in silico approach to identify factors significantly impacting mRNA and protein localization along the axon of a typical pyramidal neuron, focusing on ATP energy consumption.
We examined the influence of diffusion, active transport, degradation, translation, and bouton entrapment of CaMKIIα molecules$^{6}$ along a linear axon with a uniform presynaptic distribution. Inspired by experimental findings$^{7}$, we introduced a 56% anterograde bias in the mRNA active transport and compared it with the lack of transport bias. For each strategy, we quantified the ATP energy cost per μm for axonal mRNA and protein localization by summing the ATP costs of transcription, translation, active transport, and degradation, while varying axon lengths from 100 to 2000 μm. Our findings indicate optimal energy consumption with a bias in mRNA transport for axons that are least 830 μm long.
This integrative approach combines multiple molecular dynamic processes with axonal morphology to assess optimal ATP consumption under different active transport and synaptic distribution hypotheses. Identifying the causal factors for baseline mRNA distribution can guide new experimental designs for studying animal models of disease.