How old are dense core vesicles residing in en passant boutons: Simulation of the mean age of dense core vesicles in axonal arbors accounting for resident and transiting vesicle populations

TL;DR

This paper develops a detailed computational model to estimate the age distribution of dense core vesicles in neuronal boutons, providing insights into vesicle aging patterns and their potential role in neurodegenerative processes like Parkinson's disease.

Contribution

The study introduces a novel model that accounts for resident and transiting vesicle populations to predict vesicle age distributions in axonal boutons, aligning with experimental data.

Findings

Older vesicles are more prevalent in distal boutons.

Predicted age difference of about two hours between proximal and distal boutons.

Bimodal age density distribution of resident vesicles due to different transiting states.

Abstract

In neurons, neuropeptides are synthesized in the soma and are then transported along the axon in dense core vesicles (DCVs). DCVs are captured in varicosities located along the axon terminal called en passant boutons, which are active terminal sites that accumulate and release neurotransmitters. Recently developed experimental techniques allow for the estimation of the age of DCVs in various locations in the axon terminal. Accurate simulation of the mean age of DCVs in boutons requires the development of a model that would account for resident, transiting-anterograde, and transiting-retrograde DCV populations. In this paper, such a model is developed. The model is applied to simulating DCV transport in Drosophila type II motoneurons. The model simulates DCV transport and capture in the axon terminals and makes it possible to predict the age density distribution of DCVs in en passant boutons as well as DCV's mean age in boutons. The predicted prevalence of older organelles in distal boutons may explain the "dying back" pattern of axonal degeneration observed in dopaminergic neurons in Parkinson's disease. The predicted difference of two hours between the age of older DCVs residing in distal boutons and the age of younger DCVs residing in proximal boutons is consistent with an approximate estimate of age difference deduced from experimental observations. The age density of resident DCVs is found to be bimodal, which is because DCVs are captured from two transiting states: the anterograde transiting state that contains younger DCVs and the retrograde transiting state that contains older DCVs.