Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism

Abstract

Hyperhomocysteinaemia can contribute to cognitive impairment and brain atrophy. MTRR (methionine synthase reductase) activates methionine synthase, which catalyses homocysteine remethylation to methionine. Severe MTRR deficiency results in homocystinuria with cognitive and motor impairments. An MTRR polymorphism may influence homocysteine levels and reproductive outcomes. The goal of the present study was to determine whether mild hyperhomocysteinaemia affects neurological function in a mouse model with Mtrr deficiency. Mtrr+/+, Mtrr+/gt and Mtrrgt/gt mice (3 months old) were assessed for short-term memory, brain volumes and hippocampal morphology. We also measured DNA methylation, apoptosis, neurogenesis, choline metabolites and expression of ChAT (choline acetyltransferase) and AChE (acetylcholinesterase) in the hippocampus. Mtrrgt/gt mice exhibited short-term memory impairment on two tasks. They had global DNA hypomethylation and decreased choline, betaine and acetylcholine levels. Expression of ChAT and AChE was increased and decreased respectively. At 3 weeks of age, they showed increased neurogenesis. In the cerebellum, mutant mice had DNA hypomethylation, decreased choline and increased expression of ChAT. Our work demonstrates that mild hyperhomocysteinaemia is associated with memory impairment. We propose a mechanism whereby a deficiency in methionine synthesis leads to hypomethylation and compensatory disturbances in choline metabolism in the hippocampus. This disturbance affects the levels of acetylcholine, a critical neurotransmitter in learning and memory.

High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring

“…The thickness values for dentate gyrus are the average of three measurements per section, for four sections per mouse. Cholinergic staining was done as previously described (44) using a ChAT polyclonal goat antibody (Millipore, Billerica, USA). Positive cholinergic neurons were counted in 3–4 sections per animal (5 animals per group) in the Substantia Innominata (SI) at a magnification of 400×.…”

Deleterious Effects of Chronic Folate Deficiency in the Ts65Dn Mouse Model of Down Syndrome

“…For instance, reducing the expression of folate transporters in mice leads to a significant failure in spatial learning (Höger et al, 2009). Furthermore, mutations in the methylenetetrahydrofolate reductase (MTHFR) gene or those with deficiency in MTRR show hyperhomocysteinemia, failure in DNA methylation (Rozen, 2000), and novel object recognition impairment (Jadavji et al, 2014). Due to the essential role of folate metabolism in cognitive function and the fact that a considerable proportion of the pediatric population is exposed to suboptimal doses of folate intake, the question that was raised was whether chronic folate deficiency (CFD) could lead to exacerbation of symptoms in individuals with cognitive disability.…”

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

“…Several animal models with induced elevated levels of plasma homocysteine also exhibit impairments in short-term, spatial, and long term memory [15][16][17][18]. These impairments may be a result of the negative effects of elevated levels of homocysteine on vascular function [17,18].…”

“…Additionally, homocysteine can induce the accumulation of reactive oxygen species (ROS) in the brain [19],reduce levels of acetylcholine [15,16,20], inhibit nitric oxide [21], lead to excitotoxicity in the cell via repeated stimulation of the N-methyl-d-aspartate (NMDA) receptor [19,22], promote cytotoxicity by oxidizing membrane lipids and proteins [23,24], increase levels of apoptosis [16,25], or reduce levels of SAM [26].…”