L-glutamate and schizophrenia

NMDA receptor

Dysregulation of glutamatergic neurotransmission has been widely postulated as being involved in the etiology of schizophrenia. In the etiology of schizophrenia I have been stressing the dysregulation tricarboxylic acid (TCA) cycle via dysregulation of aconitase and the 2-oxoglutarate dehydrogenase complex stemming from shortages of coenzyme A.

The TCA cycle produces 2-oxouglutarate. .L-glutamate can be synthesized from 2-oxoglutarate. With dysregulation of the TCA cycle there can be a disruption in the synthesis of L-glutamate which would adversely affect glutamatergic neurotransmission whereby symptoms of schizophrenia could develop. .

Increasing glutamatergic neurotransmission alone via glutamate receptor agonists, however, does not solve the problem. The TCA cycle is still dysregulated.

There is strong focus on NMDA glutamate receptors in research on schizophrenia. Dysregulation of the TCA cycle, however, would dysregulate glutamatergic neurotransmission generally and also dysregulate GABA neurotransmission as GABA is synthesized from L-glutamate . D-serine which is an NMDA receptor agonist has failed in phase II trials where d-serine was being tested for effectiveness against symptoms of schizophrenia though a deuterated (i.e patenable) form of D-serine could still be effective for hair loss.

I hold that only addressing NMDA receptors will always fail in terms of the treatment of schizophrenia. Dysregulation of glutamatergic neurotransmission plays a key role in the etiology of schizophrenia, however, to address dysregulations of glutamatergic neurotransmission in schizophrenia dysregulation of the TCA cycle must be first addressed.

Pantothenic acid and acetylcholine in Alzheimer’s disease

Synthesis of acetylcholine requires acetyl-coenzyme A which donates an acetyl group to choline. With dysregulation of the transsulfuration pathway in Alzheimer’s disease, marked by high levels of homocysteine,  L-cysteine is not synthesized at sufficient levels. See my paper A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway. With low levels of l-cysteine coenzyme A, which is synthesized from pantothenic acid and which requires l-cysteine for synthesis, is not synthesized at appropriate levels. With low levels of coenzyme A the E2 subunit of the pyruvate dehydrogenase complex is underactive. Acetyl-coenzyme A required for the synthesis of acetylcholine is derived from the pyruvate dehydrogenase complex. Dysregulation of the pyruvate dehydrogenase complex could lead to shortages of acetylcholine in Alzheimer’s disease. Shortages of acetylcholine are a hallmark of Alzheimer’s disease which could be due decreases in the synthesis of coenzyme A is Alsheimer’s disesae.