Targeting the NMDA receptor subunit NR2B for treating or preventing age-related memory decline

Expert Opin Ther Targets. 2014 Oct;18(10):1121-30. doi: 10.1517/14728222.2014.941286. Epub 2014 Aug 24.


Introduction: Age-related memory loss is believed to be a result of reduced synaptic plasticity, including changes in the NR2 subunit composition of the NMDA receptor. It is known that endogenous NR2B subunits decrease as the brain ages, whereas transgenic upregulation of NR2B enhances synaptic plasticity and learning and memory in several animal species. Accumulating evidence suggests that elevated brain magnesium levels, via dietary supplementation, can boost NR2B in the brain, consequently reversing memory deficits and enhancing cognitive abilities.

Areas covered: This review highlights the convergent molecular mechanisms via the NR2B pathway as a useful strategy for treating age-related memory loss. A dietary approach, via oral intake of a novel compound, magnesium L-threonate (MgT), to boost NR2B expression in the brain is highlighted.

Expert opinion: Direct upregulation of the NR2B subunit expression can enhance synaptic plasticity and memory functions in a broad range of behavioral tasks in rodents. Other upregulation approaches, such as targeting the NR2B transporter or surface recycling pathway via cyclin-dependent kinase 5, are highly effective in improving memory functions. A dietary supplemental approach by optimally elevating the [Mg²⁺] in the brain is surprisingly effective in upregulating NR2B expression and improving memories in preclinical studies. MgT is currently under clinical trials.

Keywords: Alzheimer; NMDA receptor NR2B; NMDA receptors; Parkinson; age-related memory loss; depression; magnesium; magnesium L-threonate; memory enhancement; mild cognitive impairment; schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging / physiology
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Butyrates / administration & dosage
  • Butyrates / pharmacology
  • Cognition / drug effects
  • Dietary Supplements
  • Humans
  • Magnesium / metabolism
  • Memory / drug effects
  • Memory / physiology
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology
  • Memory Disorders / prevention & control
  • Molecular Targeted Therapy*
  • Neuronal Plasticity / drug effects
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Up-Regulation / drug effects


  • Butyrates
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Magnesium
  • threonic acid