Ascorbate Depletion Disrupts Brain Function and Behavior After Mild Traumatic Brain Injury in Mice

Abstract

Traumatic brain injuries (TBIs) possess a complex pathophysiology that often results in chronic neurological and behavioral impairments. A critical component in the progression of TBI-related cellular damage and associated functional deficits is oxidative stress, as evidenced in both human and rodent studies. Vitamin C (Ascorbate, ASC) is a necessary antioxidant in the brain and protects against oxidative stress. Dietary deficiency of ASC is of concern for humans who do not get adequate nutrition. Depleted levels of ASC have been associated with altered neuroinflammatory response, changes in neurotransmitter metabolism and increased oxidative stress, which may each contribute to the pathophysiology and cognitive change following mild TBI. Neuroinflammation is a major characteristic of pathology in TBI. Microglia, the brain’s resident myeloid cells, shift between activation states under neuroinflammatory conditions, both responding to, but also driving damage in the brain. Uptake of ASC throughout the central nervous system is facilitated by the sodium-dependent vitamin C transporter 2 (SVCT2). SVCT2 transports the reduced form of ASC into neurons and microglia, however the contribution of altered SVCT2 expression to the neuroinflammatory response in microglia is not well understood. We investigated the impact of depleted brain ASC on behavioral outcomes in mild TBI and explores the potential involvement of glutamate-related mechanisms. Our results indicate that a single mTBI event disrupted prepulse inhibition outcomes acutely in a sexually dimorphic manner, with resolution occurring at different time courses for male and female mice. We also demonstrate that SVCT2 expression modifies microglial response, as shown through changes in cell morphology and mRNA expression, following a mild TBI in mice with decreased or increased expression of SVCT2. Results were supported by in vitro studies in an immortalized microglial cell line and in primary microglial cultures derived from SVCT2-heterozygous and transgenic animals. Together these studies demonstrate the importance of SVCT2 and ASC in modulating the microglial response to mTBI and suggests a potential role for both in response to mitigate oxidative driven neuroinflammatory challenges and associated behavioral changes.