Regulation of structural and functional synapse density by L-threonate through modulation of intraneuronal magnesium concentration

Neuropharmacology. 2016 Sep;108:426-39. doi: 10.1016/j.neuropharm.2016.05.006. Epub 2016 May 10.


Oral administration of the combination of L-threonate (threonate) and magnesium (Mg(2+)) in the form of L-Threonic acid Magnesium salt (L-TAMS) can enhance learning and memory in young rats and prevent memory decline in aging rats and in Alzheimer's disease model mice. Recent results from a human clinical trial demonstrate the efficacy of L-TAMS in restoring global cognitive abilities of older adults. Previously, we reported that neuronal intracellular Mg(2+) serves as a critical signaling molecule for controlling synapse density, a key factor that determines cognitive ability. The elevation of brain Mg(2+) by oral administration of L-TAMS in intact animals plays a significant role in mediating the therapeutic effects of L-TAMS. The current study sought to elucidate the unique role of threonate. We aimed to understand if threonate acts directly to elevate intraneuronal Mg(2+), and why Mg(2+) given without threonate is ineffective for enhancing learning and memory ability. We discovered that threonate is naturally present in cerebrospinal fluid (CSF) and oral treatment with L-TAMS elevated CSF threonate. In cultured hippocampal neurons, threonate treatment directly induced an increase in intracellular Mg(2+) concentration. Functionally, elevating threonate upregulated expression of NR2B-containing NMDAR, boosted mitochondrial membrane potential (ΔΨm), and increased functional synapse density in neuronal cultures. These effects are unique to threonate, as other common Mg(2+) anions failed to have the same results. Mechanistically, threonate's effects were specifically mediated through glucose transporters (GLUTs). We also evaluated the effects of threonate in human neural stem cell-derived neurons, and found it was equally effective at upregulating synapse density. The current study provides an explanation for why threonate is an essential component of L-TAMS and supports the use of L-TAMS to promote cognitive abilities in human.

Keywords: Functional terminals; Human stem cell-derived neurons; Intracellular Mg(2+); Rat; Synaptic density; Threonate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Butyrates / blood
  • Butyrates / cerebrospinal fluid
  • Butyrates / pharmacology*
  • Cells, Cultured
  • Fetus
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Intracellular Fluid / drug effects
  • Intracellular Fluid / metabolism*
  • Magnesium / metabolism*
  • Male
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / drug effects
  • Synapses / metabolism*


  • Butyrates
  • Magnesium
  • threonic acid