Magnesium deficiency & neurological function

[This article is adapted from my recent research paper; references are not listed here.]

Introduction

The western diet is relatively deficient in magnesium, with the majority of Americans not achieving the RDA and/or consuming altered dietary Mg/Ca ratios. Magnesium deficiency has links with many conditions such as mood disorders, tourette’s, insulin resistance, cardiovascular disease and neurodegenerative disorders. Magnesium deficiency has also recently been linked to the aging process itself, since studies have shown that culture in low magnesium accelerates the senescence of human cells. Owing to magnesium’s importance in the nervous system, magnesium deficiency can reduce seizure threshold and induce epileptiform activity, and as such is often used as an animal epilepsy model. Animal models have also shown that magnesium deficiency induces depression which is reversed by SSRIs. A PMRS study reported low brain intracellular magnesium levels in MDD. Magnesium supplementation has demonstrated anxiolytic and antidepressant activity in animal models, and rapid antidepressant activity in human TRD (treatment-resistant depression). Magnesium supplementation has also been shown to facilitate learning and improve other symptoms in human dementia; and in rats elevating brain magnesium leads to the enhancement of learning abilities, working memory, and short and long-term memory.

Magnesium biology
Magnesium (Mg2+) is the second most abundant intracellular cation after potassium, and is fundamental to basic cellular metabolism. Magnesium is involved in hundreds of enzymatic reactions which participate in the metabolism of glucose, lipids, proteins, nucleic acids and DNA. In such reactions magnesium participates either by direct binding and allosteric activation, or as a magnesium-nucleotide complex (e.g. mgATP). As such magnesium is particularly involved in all reactions using nucleotides as cofactors or substrates, including hydrolases and phosphotransferases, such as ATPases and protein kinases. In such reactions, enzyme activity depends both on the ratio and absolute levels of Mg2+ and ATP. At the membrane level, magnesium is known to alter both receptor sites and transmembrane ion movements; magnesium forms complexes with phospholipids, which reduces their fluidity and permeability. Within the cell, magnesium is required for ATP and DNA synthesis, and evidence suggests magnesium is directly correlated to cellular proliferation.

NMDAR blocker
At the neurotransmission level, magnesium is vital for the NMDAR’s characteristic slow activation kinetics and co-incident detection. At membrane potentials below -40mv, Mg2+ ions bind to the NMDAR channel pore and block permeability, whereas during depolarisation Mg2+ dissociates allowing the NMDAR ion channel to open. The subunit composition of NMDARs determines the strength of Mg2+ blocking; NMDARs containing GluN2A/B subunits are similarly and most strongly blocked by Mg2+, whilst GluN2C/D containing NMDARs convey much weaker Mg2+ blocking, and GluN3 containing NMDARs have low Mg2+ blocking and low Ca2+ permeability. Therefore the Mg2+ block may be most active on presynaptic, postsynaptic and extrasynaptic neuronal NMDARs, where GluN2A/B subunits are most prevalent. Magnesium also affects the affinity of NMDAR ligands, such as increasing glycine’s affinity for the NMDAR which potentiates NMDAR activity at positive membrane potentials, and increasing glutamate’s dissociation and so enhancing NMDAR desensitisation. Magnesium (and ATP) also stimulates the serine racemase enzyme, which converts l-serine to d-serine – an astrocyte derived co-activator of NMDARs. Magnesium’s overall effects on NMDAR activity seem similar to that of ATP, in that both shift the glutamate-NMDAR response curve to the right and so ultimately act to increase the signal-to-noise ratio. Deficiency of magnesium leads to NMDAR hypersensitivity and tonic over-activation by increasing channel opening probability; such dysfunction impairs synaptic plasticity in the hippocampus, and fear conditioning in mice. Magnesium-induced NMDAR over-activation has also been shown to cause release of neuronal reduced glutathione which eventually leads to oxidative neuronal death. In the spinal cord, magnesium deficiency induces a sensitisation of nociceptive pathways (pain pathways) which is reversed by NMDAR, PKC or NOS antagonists.

Other receptor-level effects
Animal studies have connected magnesium’s neurotransmission-level activity to various other systems, such as monoaminergic and cholinergic systems. Magnesium has also been shown to increase GABAA activity and 5-HT1A receptor binding - two important inhibitory receptors that mediate anxiolytic and antidepressant activity. Magnesium is also likely to affect the activity of multiple protein kinases and thus intracellular transduction cascades, which will contribute to its memory enhancing effects in humans and animals. 

Magnesium also modulates the stress response and circadian rhythm in humans. Magnesium has been shown to lower ACTH, cortisol and catecholamines. Magnesium stimulates n-acetyltransferase activity, the penultimate enzyme in melatonin synthesis; as such magnesium deficiency has been shown to lower plasma melatonin in rats. Additionally, the product of the n-acetyltransferase reaction (n-acetyl-serotonin) also acts as a potent Trkb receptor agonist, and in similar fashion to BDNF has been shown to have strong antidepressant and neuroprotective activity. In summary, magnesium’s influence on neuronal activity may be thought of as calming and stabilising, whilst acting to increase the efficiency of signal transduction and synaptic plasticity.