Send to

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

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

Author information

School of Medicine, Tsinghua University, Beijing, 100084, China.
Neurocentria, Inc., Fremont, CA 94538, USA.
School of Medicine, Tsinghua University, Beijing, 100084, China; Neurocentria, Inc., Fremont, CA 94538, USA. Electronic address:


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.


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

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center