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

Hyperhomocysteinemia can contribute to cognitive impairment and brain atrophy. Methionine synthase reductase (MTRR) activates methionine synthase, which catalyzes 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 this study was to determine whether mild hyperhomocysteinemia impacts neurologic function in a mouse model with Mtrr deficiency. Three-month-old Mtrr+/+, Mtrr+/gt and Mtrrgt/gt mice were assessed for short-term memory, brain volumes and hippocampal morphology. We also measured DNA methylation, apoptosis, neurogenesis, choline metabolites and expression of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in hippocampus. Mtrrgt/gt mice exhibited short-term memory impairment on 2 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 cerebellum, mutant mice had DNA hypomethylation, decreased choline and increased expression of ChAT. Our work demonstrates that mild hyperhomocysteinemia 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 hippocampus. This disturba...
Source: BJ Disease - Category: Biochemistry Authors: Tags: BJ Disease Source Type: research