Ascorbic acid insufficiency impairs spatial memory formation in juvenile AKR1A-knockout mice

Abstract

AKR1A, an aldo keto reductase, is involved in the synthesis of ascorbic acid as well as the reduction of a variety of aldehyde compounds. AKR1A −/− mice produce considerably less ascorbic acid (about 10%) compared to AKR1A +/+ mice and require ascorbic acid supplementation in order to breed. To elucidate the roles played by AKR1A in spatial memory, AKR1A −/− male mice were weaned at 4 weeks of age and groups that received ascorbic acid supple mentation and no supplementation were subjected to a Morris water maze test. Juvenile AKR1A −/− mice that received no supple mentation showed impaired spatial memory formation, even though about 70% of the ascorbic acid remained in the brains of the AKR1A −/− mice at day 7 after weaning. To the contrary, the young adult AKR1A −/− mice at 13-15 weeks of age maintained only 15% of ascorbic acid but showed no significant difference in the spatial memory compared with the AKR1A +/+ mice or ascorbic acid supplemented AKR1A −/− mice. It is conceivable that juvenile mice require more ascorbic acid for the appropriate level of formation of spatial memory and that maturation of the neural system renders the memory forming process less sensitive to an ascorbic acid insufficiency.

Aldo-Keto Reductase Family 1 Member A1 (AKR1A1) Deficiency Exacerbates Alcohol-Induced Hepatic Oxidative Stress, Inflammation, Steatosis, and Fibrosis

“…Taking advantage of genetically deficient mouse models, more latent physiological functions of AKR1A1 have been revealed. Insufficient ascorbate production in AKR1A1-knockout mice leads to further metabolic pathway malfunction, eventually causing orthopedic disorder (osteopenia, spontaneous fractures and osteoporosis) [33,34], impaired formation of spatial memory in juveniles [35], aggressive behaviors [36], embryonic development and neonatal growth disabilities [37], and hepatic steatosis and injury [10][11][12][13][14]. Notably, ascorbate replenishment effectively improves these severe disorders.…”

Ascorbate Is a Primary Antioxidant in Mammals

“…Because receptors for γ-aminobutyric acid (GABA) are thought to be the likely target of pentobarbital, the influence of pentobarbital on GABA receptors may be sustained under an Asc insufficiency. Impaired spatial memory formation in juvenile AKR1A −/− mice was observed based on a water maze test, although there is no noticeable hippocampal damage or neurotransmitter contents [ 186 ].…”

Vitamin C Deficiency in the Young Brain—Findings from Experimental Animal Models

“…Alterations in pharmacologically induced functional responses supported an imbalance in the regulation of brain dopamine in vitC deficient animals [ 262 ]. In juvenile (4-week-old) akr1a −/− mice, short-term vitC depletion (1 week) impaired spatial memory, whereas this was not the case in chronically vitC deficient young adult akr1a −/− mice (12–13 weeks of age) despite lower brain ASC levels in adults vs. juveniles [ 264 ]. This may indicate that the juvenile hippocampus requires increased vitC levels during development of functional neuronal circuits, but also that, in akr1a −/− mice, the developing hippocampus may be able to compensate for the impaired spatial function over time.…”