Ascorbate deficiency decreases dopamine release in gulo^–/– and APP/PSEN1 mice

Abstract

Dopamine (DA) has important roles in learning, memory, and motivational processes and is highly susceptible to oxidation. In addition to dementia, Alzheimer's disease (AD) patients frequently exhibit decreased motivation, anhedonia, and sleep disorders, suggesting deficits in dopaminergic neurotransmission. Vitamin C (ascorbate, ASC) is a critical antioxidant in the brain and is often depleted in AD patients as a result of disease-related oxidative stress and dietary deficiencies. To probe the effects of ASC deficiency and AD pathology on the DAergic system, gulo -/mice, which like humans depend on dietary ASC to maintain adequate tissue levels, were crossed with APP/PSEN1 mice and provided sufficient or depleted ASC supplementation from weaning until 12 months of age. Ex vivo fast-scan cyclic voltammetry showed that chronic ASC depletion and APP/PSEN1 genotype both independently decreased dopamine release in the nucleus accumbens, a hub for motivational behavior and reward, while DA clearance was similar across all groups. In striatal tissue containing nucleus accumbens, low ASC treatment led to decreased levels of DA and its metabolites 3,4-dihydroxyohenyl-acetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA). Decreased enzyme activity observed through lower pTH/TH ratio was driven by a cumulative effect of ASC depletion and APP/PSEN1 genotype. Together the data show that deficits in dopaminergic neurotransmission resulting from age and disease status are magnified in conditions of low ASC which decrease DA availability during synaptic transmission. Such deficits may contribute to the non-cognitive behavioral changes observed in AD including decreased motivation, anhedonia, and sleep disorders.

Vitamin C Differentially Impacts the Serum Proteome Profile in Female and Male Mice

“…Clinically relevant animal models of vitamin C (ascorbate) synthesis deficiency are essential for improving our understanding of the role of ascorbate in the pathogenesis of complex diseases . In this context, the Gulo –/– mouse is a relevant model to examine the impact of ascorbate on different biological processes in vivo . − Importantly, the levels of ascorbate found in the serum of Gulo –/– mice will reflect the amounts of ascorbate provided in drinking water. Moreover, it was found that serum ascorbate concentrations showed a sigmoid-shaped dose–response curve similar to that observed in human studies. , By simply changing the amount of ascorbate in drinking water, we can control the concentration of ascorbate in the serum of these mice in a noninvasive manner and study its impact on different biological processes in vivo .…”

L-Ascorbic Acid Shapes Bovine Pasteurella multocida Serogroup A Infection

“…Consistent with previous results that the infected lung has less AA than the infected liver, higher OmpA expression was detected in the infected lung than the infected liver ( Figure 3D ). Unlike humans who rely on exogenous AA to meet physiological needs, mouse and cattle are capable to synthetize enough AA for themselves through a special gene Gulo , which only expresses in the liver ( 45 , 46 ). Downregulation of Gulo expression is then found in the infected liver, indicating that AA biogenesis was damaged under bovine PmA infection ( Figure 3E ).…”

Dietary Vitamin C and Age-Induced Lipid and Hormonal Metabolic Changes in a Humanized Mouse Model Not Synthesizing Vitamin C and Producing Lipoprotein(a) [Gulo (−/−); Lp(a)+]

“…In our previous study on Gulo (−/−) and Lp(a) mice, we found a reverse relationship between serum ascorbic acid levels and serum total cholesterol and LDL levels after a sixweek low-vitamin-C regimen [5]. e effects of vitamin C intake on lowering serum LDL have been demonstrated in guinea pigs, Gulo (−/−) mice, and humans [10,[26][27][28][29][30][31]. It has been shown that daily supplementation of 500 mg vitamin C is effective in reducing serum cholesterol and serum LDL levels in humans [32].…”

“…With rare Lp(a) representation in the animal world, the animal models for the study of Lp(a) metabolism and pathogenicity are scarce, mostly limited to transgenic rabbit and mouse models [7,8]. Experimental studies on vitamin C in various aspects related to human metabolism have been largely conducted on guinea pigs and a recently developed mouse model lacking gulonolactone oxidase activity, Gulo (−/−) [9][10][11]. To our knowledge, only the transgenic mouse model, Gulo (−/−) and Lp(a)+, that we developed combines these two important characteristics of human metabolism in one organism.…”