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Research Papers

Simulating Reversibility of Dense Core Vesicles Capture in En Passant Boutons: Using Mathematical Modeling to Understand the Fate of Dense Core Vesicles in En Passant Boutons

[+] Author and Article Information
I. A. Kuznetsov

Perelman School of Medicine,
University of Pennsylvania,
Philadelphia, PA 19104;
Department of Bioengineering,
University of Pennsylvania,
Philadelphia, PA 19104
e-mail: ivan.kuznetsov@uphs.upenn.edu

A. V. Kuznetsov

Department of Mechanical and Aerospace
Engineering,
North Carolina State University,
Raleigh, NC 27695-7910
e-mail: avkuznet@ncsu.edu

Manuscript received May 30, 2017; final manuscript received September 17, 2017; published online February 26, 2018. Assoc. Editor: Guy M. Genin.

J Biomech Eng 140(5), 051004 (Feb 26, 2018) (12 pages) Paper No: BIO-17-1231; doi: 10.1115/1.4038201 History: Received May 30, 2017; Revised September 17, 2017

The goal of this paper is to use mathematical modeling to investigate the fate of dense core vesicles (DCVs) captured in en passant boutons located in nerve terminals. One possibility is that all DCVs captured in boutons are destroyed, another possibility is that captured DCVs can escape and reenter the pool of transiting DCVs that move through the boutons, and a third possibility is that some DCVs are destroyed in boutons, while some reenter the transiting pool. We developed a model by applying the conservation of DCVs in various compartments composing the terminal, to predict different scenarios that emerge from the above assumptions about the fate of DCVs captured in boutons. We simulated DCV transport in type Ib and type III terminals. The simulations demonstrate that, if no DCV destruction in boutons is assumed and all captured DCVs reenter the transiting pool, the DCV fluxes evolve to a uniform circulation in a type Ib terminal at steady-state and the DCV flux remains constant from bouton to bouton. Because at steady-state the amount of captured DCVs is equal to the amount of DCVs that reenter the transiting pool, no decay of DCV fluxes occurs. In a type III terminal at steady-state, the anterograde DCV fluxes decay from bouton to bouton, while retrograde fluxes increase. This is explained by a larger capture efficiency of anterogradely moving DCVs than of retrogradely moving DCVs in type III boutons, while the captured DCVs that reenter the transiting pool are assumed to be equally split between anterogradely and retrogradely moving components. At steady-state, the physiologically reasonable assumption of no DCV destruction in boutons results in the same number of DCVs entering and leaving a nerve terminal. Because published experimental results indicate no DCV circulation in type III terminals, modeling results suggest that DCV transport in these type III terminals may not be at steady-state. To better understand the kinetics of DCV capture and release, future experiments in type III terminals at different times after DCV release (molting) may be proposed.

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Figures

Grahic Jump Location
Fig. 1

A schematic diagram showing a nerve terminal with two branches. Each branch contains four boutons. We numbered the boutons as in Wong et al. [5]. We also show five compartments simulated in the model (four compartments occupied by the boutons and the compartment representing the axon), as well as dimensions of these compartments.

Grahic Jump Location
Fig. 2

A kinetic diagram showing DCV fluxes between the five compartments simulated in the model, resident and transiting DCVs in the boutons as well as transiting DCVs in the axon. Fluxes between the compartments are shown by regular arrows while fluxes simulating DCV capture into the resident state are shown by block arrows.

Grahic Jump Location
Fig. 3

The buildup toward steady-state: concentrations of captured DCVs in various boutons: (a) terminal with type Ib boutons and (b) terminal with type III boutons; δ=1 (all captured DCVs eventually reenter the circulation)

Grahic Jump Location
Fig. 4

The buildup toward steady-state: concentrations of transiting DCVs in the axon: (a) terminal with type Ib boutons and (b) terminal with type III boutons; δ=1 (all captured DCVs eventually reenter the circulation)

Grahic Jump Location
Fig. 5

Fluxes between the axon and the most proximal bouton and between various boutons at the initial state and at steady-state: (a) terminal with type Ib boutons and (b) terminal with type III boutons; δ=1 (all captured DCVs eventually reenter the circulation)

Grahic Jump Location
Fig. 6

The buildup toward steady-state: fluxes between various boutons and between the axon and the most proximal bouton: (a) terminal with type Ib boutons and (b) terminal with type III boutons; δ=1 (all captured DCVs eventually reenter the circulation)

Grahic Jump Location
Fig. 7

The build up toward steady-state: the expansion of Fig.6 between 0 and 1.5 h: (a) terminal with type Ib boutons and (b) terminal with type III boutons; δ=1 (all captured DCVs eventually reenter the circulation)

Grahic Jump Location
Fig. 8

Similar to Fig. 3, but now for δ=0.5 (half of captured DCVs are destroyed in boutons and half reenter the circulation): (a) terminal with type Ib boutons and (b) terminal with type III boutons

Grahic Jump Location
Fig. 9

Similar to Fig. 4, but now for δ=0.5 (half of captured DCVs are destroyed in boutons and half reenter the circulation): (a) terminal with type Ib boutons and (b) terminal with type III boutons

Grahic Jump Location
Fig. 10

Similar to Fig. 5, but now for δ=0.5 (half of captured DCVs are destroyed in boutons and half reenter the circulation): (a) terminal with type Ib boutons and (b) terminal with type III boutons

Grahic Jump Location
Fig. 11

Similar to Fig. 6, but now for δ=0.5 (half of captured DCVs are destroyed in boutons and half reenter the circulation): (a) terminal with type Ib boutons and (b) terminal with type III boutons

Grahic Jump Location
Fig. 12

Similar to Fig. 7, but now for δ=0.5 (half of captured DCVs are destroyed in boutons and half reenter the circulation): (a) terminal with type Ib boutons and (b) terminal with type III boutons

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