Behavioral alterations are associated with vitamin B12 deficiency in the transcobalamin receptor/CD320 KO mouse

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.

Neuropathology of vitamin B12deficiency in theCd320−/−mouse

“…of Cd320 2/2 mice corrected some of the hematologic parameters, such as HGB, HCT, and RDW but did not correct or worsen the neuropathology. Although, the levels of Cbl in the Cd320 2/2 mouse liver and spleen were lower, they were not as severely depleted as in the brain and SC, suggesting an alternate pathway for Cbl uptake in these organs if additional Cbl is available through diet (23,24). Furthermore, lack of Cbl uptake in the CNS of the Cd320 2/2 mouse fed a normal diet contributes to elevated TC-Cbl in the blood and results in increased Cbl in the kidneys via uptake by megalin (3).…”

“…Six groups of C57BL/6J wild-type (Cd320 +/+ ) and TCblR/Cd320knockout (Cd320 2/2 ) [C57BL/6J-Cd320Gt(pGt01xft2)Qua] mice, 5-mo-old males and females (1:1 ratio), backcrossed twice on a C57BL/6J background, were used. The age of the mice for the study was based on the observation of severe CNS Cbl deficiency in the Cd320 2/2 mice and systemic Cbl deficiency after 3 mo of consuming a Cbl-deficient diet and the observation of behavioral deficits in 5-mo-old mice (23,24). The wild-type C57BL/6J mice (Cd320 +/+ ) used in the study were derived from a wild-type litter, and the Cd320 2/2 were generated by breeding homozygous mice.…”

“…room temperature for 10 min in recording aCSF (same composition as dissection aCSF, but containing 1.5 mM MgSO 4 and 2.5 mM CaCl 2 ) and then transferred into an interface recording chamber with flowing recording aCSF (4 ml/min) saturated with 95% O 2 and 5% CO 2 at 37°C (23). Both SNs were laid out straight across the extension of the recording chamber and separated from each other.…”

“…The TCblR/Cd320 2/2 mouse exhibits behavioral deficits, including cognitive deficits, also seen in the human condition. This mouse model is associated with decreased expression of the a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid synaptic receptor subunit glutamate receptor-1 with a significant decrease in hippocampal pyramidal cell nuclei and brain mass (23). Because the Cd320 2/2 mouse fed a Cbl replete diet develops Cbl deficiency in the nervous system, in this study, we examined the effects of Cbl deficiency by dietary restriction and by ablating the receptor for cellular uptake of the vitamin in the C57BL/6J strain and examined changes in metabolites, the SC, and the peripheral nervous system, to identify structural changes responsible for the clinical phenotype of neurologic manifestations, such as the loss of peripheral sensation and motor deficits that is seen in humans.…”

Transcellular transport of cobalamin in aortic endothelial cells

“…One of the researchers (E.V.Q.) has generated and characterized Cbl transport in a knockout mouse model of the TC receptor CD320 (95)(96)(97). Surprisingly, the CD320 knockout mice did not exhibit systemic Cbl deficiency, which suggested marked differences in Cbl transport between rodents and humans.…”