Quantitative in silico Analysis of Neurotransmitter Pathways Under Steady State Conditions

Abstract

The modeling of glutamate/GABA-glutamine cycling in the brain tissue involving astrocytes, glutamatergic and GABAergic neurons leads to a complex compartmentalized metabolic network that comprises neurotransmitter synthesis, shuttling, and degradation. Without advanced computational tools, it is difficult to quantitatively track possible scenarios and identify viable ones. In this article, we follow a sampling-based computational paradigm to analyze the biochemical network in a multi-compartment system modeling astrocytes, glutamatergic, and GABAergic neurons, and address some questions about the details of transmitter cycling, with particular emphasis on the ammonia shuttling between astrocytes and neurons, and the synthesis of transmitter GABA. More specifically, we consider the joint action of the alanine-lactate shuttle, the branched chain amino acid shuttle, and the glutamine-glutamate cycle, as well as the role of glutamate dehydrogenase (GDH) activity. When imposing a minimal amount of bound constraints on reaction and transport fluxes, a preferred stoichiometric steady state equilibrium requires an unrealistically high reductive GDH activity in neurons, indicating the need for additional bound constants which were included in subsequent computer simulations. The statistical flux balance analysis also suggests a stoichiometrically viable role for leucine transport as an alternative to glutamine for replenishing the glutamate pool in neurons.

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

“…This raises the question of how nitrogen balance is maintained in the cerebral glutamine- and glutamine-GABA cycles. Various nitrogen shuttles from neurons to astrocytes have recently been analyzed by Calvetti and Somersalo [ 154 ]. A commentary of this work has been published [ 155 ] and is summarized here.…”

Flux-Balance Based Modeling of Biofilm Communities

“…Generally, v = v(c) through a constitutive law which depends on kinetics, and kinetics parameters, of the metabolic reactions. However, using the steady state assumption of metabolic pathway analysis, equation (7) reduces to…”

“…The idea is solve (8) for v rather than solve (7) plus constitutive law v = v(c) for c, as (8) is parameter free other than known stoichiometric coefficients in S, and knowledge of reaction fluxes is sufficient to characterize biomass production as well as influx and outflux of metabolites from cells. As a consequence though, internal metabolite concentrations c, even at steady state, are unknown.…”

“…The bioengineering community has, in response to these difficulties, introduced largely kinetics-free formulations at the cellular level, termed metabolic pathway (or metabolic constraint-based) analysis [4,5,35,44] based on genomics and other omics (e.g., transcriptomics) derived data. Here we present a framework to incorporate kinetics-free methods into full scale microbial communities, biofilm models in particular, in part building on related methods previously applied to compartment models of eukaryotic cells [6,7]. The key revision is to replace classical kinetics functions entirely by cell-level steady state metabolic pathway models -this is where omics meets community.…”

Life sciences through mathematical models

“…The sampling can be done using tools from computational statistics (Heino et al 2010). In a recent article (Calvetti and Somersalo 2013), the approach was employed to shed some light on the question, how neurons and astrocytes shuttle amino groups between them to compensate the amino group imbalance due to the glutamate/GABA/ glutamine neurotransmitter cycling between the cells.…”