Plasticity of Carbohydrate Transport at the Blood-Brain Barrier.

Ellen Mcmullen,Holger M Becker,Astrid Weiler,Stefanie Schirmeier

doi:10.3389/fnbeh.2020.612430

Ellen Mcmullen, Holger M Becker + Show 2 more

Open Access

https://doi.org/10.3389/fnbeh.2020.612430

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Abstract

Neuronal function is highly energy demanding, requiring efficient transport of nutrients into the central nervous system (CNS). Simultaneously the brain must be protected from the influx of unwanted solutes. Most of the energy is supplied from dietary sugars, delivered from circulation via the blood-brain barrier (BBB). Therefore, selective transporters are required to shuttle metabolites into the nervous system where they can be utilized. The Drosophila BBB is formed by perineural and subperineurial glial cells, which effectively separate the brain from the surrounding hemolymph, maintaining a constant microenvironment. We identified two previously unknown BBB transporters, MFS3 (Major Facilitator Superfamily Transporter 3), located in the perineurial glial cells, and Pippin, found in both the perineurial and subperineurial glial cells. Both transporters facilitate uptake of circulating trehalose and glucose into the BBB-forming glial cells. RNA interference-mediated knockdown of these transporters leads to pupal lethality. However, null mutants reach adulthood, although they do show reduced lifespan and activity. Here, we report that both carbohydrate transport efficiency and resulting lethality found upon loss of MFS3 or Pippin are rescued via compensatory upregulation of Tret1-1, another BBB carbohydrate transporter, in Mfs3 and pippin null mutants, while RNAi-mediated knockdown is not compensated for. This means that the compensatory mechanisms in place upon mRNA degradation following RNA interference can be vastly different from those resulting from a null mutation.

Highlights

To allow full functionality the brain requires a lot of energy
The only two carbohydrate transporters identified in the Drosophila central nervous system (CNS) Tret1-1 and Glut1, are expressed in the perineurial glial cells or the neurons, respectively
To this end we performed a small, biased RNA interference-based screen, in which we knocked down putative carbohydrate transporters encoded in the Drosophila genome in the glial cells [genes with a predicted sugar transport function according to protein domain annotations from InterPro and UniProt, Supplementary Table 1]

Summary

Introduction

To allow full functionality the brain requires a lot of energy. Most of the energy used in the nervous system is gained via carbohydrate metabolism. The human adult brain, despite accounting for only 2% of the bodies overall mass, consumes ∼20% of the total oxygen (Mink et al, 1981; Laughlin et al, 1998; Harris et al, 2012). The oxygen is used to metabolize large amounts of glucose. The human brain uses about 90 g of glucose per day; during childhood carbohydrate usage is even higher (Kuzawa et al, 2014). The blowfly retina consumes ∼10% of the total ATP produced, which is close to the consumption observed in vertebrates (Laughlin et al, 1998)

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