GAD1 Gene Mutations: Potential Problems with Glutamate

I have previously reported on the issue of glutamate excitotoxicity. This article is a brief exploration of GAD1, an important gene that is involved in the conversion of the excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA.

The issue of glutamate toxicity is well understood. In essence, glutamate can result in cell programmed death when there is an over-abundance of it in the system. Glutamate can be overloaded for a number of reasons:

• Mutations in certain genes, which delay or augment the rate of glutamate’s utilization and fate
• Diet containing glutamate toxins such as MSG
• Microglial immune cell release of glutamate as part of an inflammatory cascade
• Induction of free glutamate due to increased detoxification reactions, specifically the increased oxidation of glutathione
• Increased utilization of folate, which contain glutamic acid conjugates

GAD1 is an interesting gene that is involved in the biosynthesis of GABA, a very important, inhibitory neurotransmitter. Genetic variations in GAD1 may involve varying degrees of glutamate excess and toxicity. GAD1 mutations are most associated with the autoantigen (another name for an autoimmune target) and T-cell target for the pancreas. Mutations of GAD1 are associated with Type 1 diabetes (1). GAD1 is also associated with a seizure disorder called “pyridoxine-dependency with seizures”. From clinical observations, individuals with genetic variations of GAD1 SNPs are more prone to mood and behavior disorders such as anxiety and OCD.

An in vitro study found that B-6 acts to improve the function of GAD1 and increase GABA (2). The primary nutrient cofactor for GAD1 is Vitamin B-6, pyridoxine.

As a cofactor, B-6 is often useful as a mood stabilizer. I often use higher doses of B-6 in combination with 5-HTP and zinc as a means to modulating serotonin and GABA. I may use higher doses of B-6 in combination with L-tyrosine or phenylalanine to promote dopamine synthesis.

Problems with how Vitamin B-6 gets utilized in the biochemistry is known to occur. Inflammatory mechanisms are known to cause B-6 deficiency (3).

A condition known as pyroluria or pyrrole disorder is strongly associated with B-6 deficiency (4).

Deficiencies of Vitamin B-6 will have detrimental effects on the brain, resulting in neurotransmitter imbalances, and the associated symptoms of mood and behavior conditions.