Regulation of Vitamin C Transport in Brain

Abstract

Vitamin C (VC) concentration in the brain is crucial for neuronal defense against oxidative stress and proper function. VC transport is a balance between regulated uptake mechanisms that include the Sodium-dependent Vitamin C Transporter, Type 2 (SVCT2) and efflux mechanisms that may involve several types of trans-membrane proteins. Neuronal function, and ultimately neurobehavioral defects, may result from dysregulation in acute uptake or efflux processes. However, the mechanisms that explain the relationships between these phenomena are yet to be understood. Thus, our overarching hypothesis is that vitamin C transport is tightly regulated in functional areas of the neuron, specifically, the nerve terminal.

First, we sought to determine whether oxidative stress could contribute to neurobehavioral defects in mice unable to synthesize VC or partially lacking the SVCT2. Our results showed that combined dietary VC and vitamin E (VE) deprivation only minimally increased neuronal oxidative stress markers compared to single deficiencies. Yet, with combined VC and VE deficiency in addition to decreased cellular uptake of VC (SVCT2+/-), deficits in motor and coordination skills became evident. Whereas this effect may be an early manifestation of scurvy, its mechanism does not appear to be due to an increase in neuronal lipid peroxidation and remains to be determined. It is clear, however, that SVCT2 function contributes to the neurobehavioral phenotype in mice.

Next, we investigated the regulation mechanisms involved in acute VC transport at the cortical nerve terminal. Using synaptosomes as a model, our immunoblot studies demonstrate that SVCT2 protein is expressed predominately at the pre-synaptic terminal while our transport studies conclude that it functions to mediate VC uptake at the synapse. While the mechanisms for VC efflux are not completely clear, our studies suggest that Volume-Regulated Anion Channels (VRACs) are likely to have a substantial role in mediating glutamate-induced VC efflux at the cortical nerve terminal. These data may extend the current hetero-exchange theory, which was established in astrocytes, to include neurons as well. Altogether, this body of work has implications in understanding the mechanisms involved in VC regulation and how they contribute to proper neuronal function.