Abstract
Vitamin B12 (cobalamin) deficiency is prevalent worldwide and causes megaloblastic anemia and neurologic deficits. While the anemia can be treated, the neurologic deficits can become refractive to treatment as the disease progresses. Therefore, timely intervention is critical for a favorable outcome. Moreover, the metabolic basis for the neuro-pathologic changes and the role of cobalamin deficiency in the pathology still remains unexplained. Using a transcobalamin receptor / CD320 knockout mouse that lacks the receptor for cellular uptake of transcobalamin bound cobalamin, we aimed to determine whether cobalamin deficiency in the central nervous system produced functional neurologic deficits in the mouse that would parallel those observed in humans. Our behavioral analyses indicate elevated anxiety and deficits in learning, memory and set-shifting of a spatial memory task in the KO mouse. Consistent with the behavioral deficits, the knockout mouse shows impaired expression of the early phase of hippocampal long-term potentiation along with reduced expression of GluR1, decreased brain mass and a significant reduction in the size of nuclei of the hippocampal pyramidal neurons. Our study suggests that the CD320 knockout mouse develops behavioral deficits associated with cobalamin deficiency and therefore could provide a model to understand the metabolic and genetic basis of neuro-pathologic changes due to cobalamin deficiency.
Highlights
Vitamin B12 is an important vitamin cofactor essential for cytosolic and mitochondrial metabolic reactions [1,2]
To understand the etiology of the neurologic disorder associated with Cbl deficiency, we investigated a mutant mouse in which the transcobalamin receptor (TCblR) gene (CD320) was ablated [10]
For the characterization of the behavioral performance of TCblR/CD320 KO (KO) mouse, in some of the studies we added two more experimental groups: (1) Wild type (WT) mice fed with a Cbl deficient diet (WT-Cbl) and (2) KO mice fed a folate supplement diet (KO+F)
Summary
Vitamin B12 (cobalamin, Cbl) is an important vitamin cofactor essential for cytosolic and mitochondrial metabolic reactions [1,2]. Cbl deficiency is a common cause of megaloblastic anemia [4]. Behavioral alterations in vitamin B12 deficiency such as dementia and cognitive impairment, which adversely affect learning and memory [5,6] and, produces anxiety [7,8]. Hematologic and neurologic symptoms do not always appear to be comorbid because in some studies, the hematologic or neurologic symptoms were present in most of Cbl deficient patients but not necessarily coexisting in the same patient [9]. While the etiology of megaloblastic anemia is well known [4], the cause of neurologic abnormalities due to Cbl deficiency is still unclear [10]
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