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.

Schizophrenia, toxoplasma gondii and iron-responsive protein 1

toxoplasma gondii

The Odd Ratio for schizophrenia for indivduals with IgG antibodies for toxoplasma gondii were 1.81, With toxoplasma gondii infection.there is increased activity of iron-responsive protein 1 (IRP1). Aconitase 1 is a dual fuction protein, When iron levels are low aconitase 1 looses and iron sulfur cluster and becomes IRP1 but when iron levels are increased IRP1 gains an iron-sulfur cluster and becomes aconitase 1. Aconitase 1 is an enzyme in the tricarboxylic acid (TCA) cycle. Increased levels of IRP1 would indicate that the TCA cycle is dysregulated which could set the set the stage for schizophrenia. See my paper Treatment-resistant schizophrenia: focus on the transsulfuration pathway. on how dysregulation of IRP1, aconitase 1 and the TCA cyle could play a part in the development of schizophrenia.

Regulation of iron metabolism by the transsulfuration pathway

top – ACO1; bottom – iron regulatory protein 1 bound to an mRNA

Iron metabolism is regulated by hepicidin, ferroportin and iron regulatory proteins. Aconitase 1 (ACO1) is a dual function protein that serves as an aconitase, which is an enzyme in the TCA cycle, when ACO1 has a 4Fe-4S iron sulfur cluster and as iron regulatory protein 1 when ACO1 looses a 4Fe-4S cluster. The sulfur for iron-sulfur clusters is derived from L-cysteine.

L-cysteine is synthesized from homocyteine via the transsulfuration pathway. Dysregulation of the transsufuration pathway by dysregulating L-cysteine synthesis could dysregulate iron-sulfur cluster formation thereby dyseregulating iron regulatory protein 1 and iron homestasis.

High homocysteine levels are present in a lot of illnesses, for example, schizophrenia, Parkinson’s disease, Alzheimer’s disease and bipolar disorder. A key part of the difficulties that arise from high homocysteine levels could be due to dysregulation of iron homeostasis.

Iron, aconitase 1, glutamate and schizophrenia

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Diminished glutamatergic neurotransmission is present in schizophrenia. N-methyl-D-aspartate receptor antagonists such as ketamine, can induce symptoms of acute schizophreniaIron.

Iron increases glutamate secretion by increasing cytosolic aconitase activity. The synthesis of isocitrate by cytosolic aconitase is the the first step in a three step synthesis of glutamate. Glutamate, arising from increases in cytosolic aconitase due to increases in iron, is secreted via the cystine/glutamate antiporter where at the same time cystine is imported into cells increasing glutathione levels in cells.

With iron supplementation in schizophrenia via iron carbonyl taken three times a day there could be increased glutamatergic neurotransmission via increases is secreted glutamate where at the same time there would be increases in cystine in cells and thereby increases in glutathione levels in cells. Supplementation with iron from iron carbonyl could be part the treatment of schizophrenia.

Aconitase 1 is decreased in Alzheimer’s disease

There is a significant decrease in the expression of aconitase 1 in blood mononuclear cells in patients with Alzheimer’s disease compared to controls. There is also a significant decrease in amyloid precursor protein (APP) in blood mononuclear cells in patients with Alzheimer’s disease compared to controls which fits with low levels of ACO1. With low levels of ACO1 there are high levels of IRP1. The 5′-untranslated region of APP mRNA contains an iron responsive element which when bound by IRP1 decreases stability of APP mRNA.

Measures to improve TCA cycle metabolism could benefit AD patients

Ann Neurol. 2005 May;57(5):695-703.
Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE.

Abstract

Reductions in cerebral metabolism sufficient to impair cognition in normal individuals also occur in Alzheimer’s disease (AD). The degree of clinical disability in AD correlates closely to the magnitude of the reduction in brain metabolism. Therefore, we tested whether impairments in tricarboxylic acid (TCA) cycle enzymes of mitochondria correlate with disability. Brains were from patients with autopsy-confirmed AD and clinical dementia ratings (CDRs) before death. Significant (p < 0.01) decreases occurred in the activities of the pyruvate dehydrogenase complex (-41%), isocitrate dehydrogenase (-27%), and the alpha-ketoglutarate dehydrogenase complex (-57%). Activities of succinate dehydrogenase (complex II) (+44%) and malate dehydrogenase (+54%) were increased (p < 0.01). Activities of the other four TCA cycle enzymes were unchanged. All of the changes in TCA cycle activities correlated with the clinical state (p < 0.01), suggesting a coordinated mitochondrial alteration. The highest correlation was with pyruvate dehydrogenase complex (r = 0.77, r2= 0.59). Measures to improve TCA cycle metabolism might benefit AD patients.

Bill Gates is looking for new ideas on the etiology of Alzheimer’s disease. A heightened focus on the TCA citric acid cycle in Alzheimer’s disease is a new approach to the etiology of Alzheimer’s disease for which there is experimental backing.

Aconitase 1 and on-off disorders

Aconitase 1 (ACO1) is an enzyme in the citric acid cycle. Aconitase 1 is a dual function protein. Upon loss of an iron-sulfur cluster ACO1  becomes iron regulatory protein 1 (IRP1).  IRP1 affects stability of mRNA transcripts of proteins involved in iron metabolism such as ferritin, DMT1, which is an iron transporter, and ferroportin, which is the only known iron exporter.   Increasing iron levels switches IRP1 to ACO1 as IRP1 gains an iron-sulfur cluster. With a 4Fe-4S iron-sulfur cluster ACO1 can participate in the citric acid cycle and generate ATP.

On-off disorders could be are due to wide swings in ACO1/IRP1 and the TCA cycle. Suddenly the TCA cycle is functioning and then the TCA cycle is not functioning while at the same time there are swings in the regulation of iron regulated proteins. Dietary iron could be associated with swings in on-off symptoms.An added wrinkle is  that high IRP1 levels adversely affects copper absorption, however, copper is needed for iron metabolism.

I very much like answers that answer everything. On-off symptoms are prominent in lots and lots of illnesses. There is, of course, bipolar disorder but a lot of depressions cycle rapidly and are some of the most difficult depressions to treat.  Parkinson’s disease has a very prominent on-off symptoms.  In Parkinson’s disease there are  indications that iron metabolism is  dysregulated. There could be a unitary explanation for cycling disorders.