Increased homocysteine levels impair reference memory and reduce cortical levels of acetylcholine in a mouse model of vascular cognitive impairment

Behav Brain Res. 2017 Mar 15:321:201-208. doi: 10.1016/j.bbr.2016.12.041. Epub 2017 Jan 11.


Folates are B-vitamins that are vital for normal brain function. Deficiencies in folates either genetic (methylenetetrahydrofolate reductase, MTHFR) or dietary intake of folic acid result in elevated levels of homocysteine. Clinical studies have shown that elevated levels of homocysteine (Hcy) may be associated with the development of dementia, however this link remains unclear. The purpose of this study was to evaluate the impact of increased Hcy levels on a mouse model of vascular cognitive impairment (VCI) produced by chronic hypoperfusion. Male and female Mthfr+/+ and Mthfr+/- mice were placed on either control (CD) or folic acid deficient (FADD) diets after which all animals underwent microcoil implantation around each common carotid artery or a sham procedure. Post-operatively animals were tested on the Morris water maze (MWM), y-maze, and rotarod. Animals had no motor impairments on the rotarod, y-maze, and could learn the location of the platform on the MWM. However, on day 8 of testing of MWM testing during the probe trial, Mthfr+/- FADD microcoil mice spent significantly less time in the target quadrant when compared to Mthfr+/- CD sham mice, suggesting impaired reference memory. All FADD mice had elevated levels of plasma homocysteine. MRI analysis revealed arterial remodeling was present in Mthfr+/- microcoil mice not Mthfr+/+ mice. Acetylcholine and related metabolites were reduced in cortical tissue because of microcoil implantation and elevated levels of homocysteine. Deficiencies in folate metabolism resulting in increased Hcy levels yield a metabolic profile that increases susceptibility to neurodegeneration in a mouse model of VCI.

Keywords: Acetylcholine; Chronic hypoperfusion; Folic acid; Homocysteine; Methylenetetrahydrofolate reductase; Vascular cognitive impairment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Animals
  • Cerebral Cortex / blood supply
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / metabolism*
  • Dementia, Vascular / diagnostic imaging
  • Dementia, Vascular / metabolism*
  • Disease Models, Animal
  • Female
  • Folic Acid Deficiency / diagnostic imaging
  • Folic Acid Deficiency / metabolism
  • Folic Acid Deficiency / psychology
  • Homocysteine / metabolism*
  • Male
  • Memory / physiology*
  • Methylenetetrahydrofolate Reductase (NADPH2) / deficiency
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / physiology
  • Neovascularization, Pathologic / diagnostic imaging
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / psychology
  • Random Allocation


  • Homocysteine
  • MTHFR protein, mouse
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Acetylcholine