Sometimes the Parts are Greater than the Whole

Schizophrenia is a psychiatric disorder that has puzzled physicians and scientists for decades. Throughout the years, copious amounts of research has been performed in an attempt to better understand the biochemistry underlying the condition, and while various treatments have been developed, we are still a long ways away from fully understanding its causes. The article written by Dean, et al., points out that schizophrenia is not a singular condition but rather a conglomeration of various disorders. For this reason, the authors postulate that in order to truly understand the underlying biochemistry, research should focus on studying these contributing disorders individually, rather than as a whole.

Previous research on the metabolome of the human central nervous system implied a relationship between the conditions that make up Schizophrenia and alterations in the manner by which glucose is metabolized. This relationship can be explained by the fact that despite having the highest energy requirement of any cell type, neurons do not have access to stores of glycogen and must obtain energy for cellular processes directly from glucose. Therefore, alterations to the metabolism of glucose via glycolysis and the citric acid cycle could produce drastic neurological effects that could contribute to the pathophysiology of schizophrenia. This notion is further supported by other previous research which revealed low levels of activity from three citric acid cycle enzymes in the prefrontal cortex, and low levels of two other enzymes involved in glucose metabolism in the hippocampus of subjects with schizophrenia. The authors of this paper noted that previously performed neuroimaging studies had indicated changes in glucose metabolism in the striatum of afflicted subjects, however this research had yet to be followed up with post-mortem studies. Therefore, the authors set out to measure the activity and levels of glycolytic and citric acid cycle enzyme, as well as specific metabolites of glucose from the striata of post-mortem subjects with schizophrenia.

Figure 1: A schematic diagram showing the components of glucose metabolism focused on in the experiments reported by this paper.

Following along with their ideology that the individual conditions which are clustered together under the term Schizophrenia should be studied independently, the authors chose to compare un-afflicted control subjects to subjects with two specific types of Schizophrenia: Muscarinic Receptor Deficit Schizophrenia (MRDS) and non-Muscarinic Receptor Deficit Schizophrenia (non-MRDS). In previous publications, the authors defined MRDS as a form of Schizophrenia in which there was a widespread loss of the cortical muscarinic receptor. In order to analyze potential differences between glucose metabolism in control, MRDS and non-MRDS subjects, the authors set out to quantify the amounts of b-subunit of Pyruvate Dehydrogenase Complex (PDHB), as well as Glucose, Pyruvate, Lactate, and Acetyl CoA in their striata. In order to quantify the levels of PDHB, they performed Western Blots on tissue samples using an anti-human PDHB antibody. They then integrated the intensity of the resultant protein bands in order to obtain numerical data. In order to determine the levels of Glucose, Pyruvate, Lactate, and Acetyl CoA, the authors made use of previously developed and manufactured analysis kits.

The authors discovered that there was little difference in the levels of PDHB, Pyruvate, Acetyl CoA and Glucose between samples collected from the control subjects and those collected from subjects with MRDS. The only metabolic difference that they discovered in MRDS subjects was a 17% increase in their levels of Lactate in comparison to the control subjects. The authors point out that this increase in Lactate could simply be due to the samples coming from postmortem subjects as other studies have indicated that blood and cerebellum levels of Lactate increase after death. When the authors compared samples of striata taken from non-MRDS subjects with samples from the control subjects, they obtained much more striking results. The samples from non-MRDS subjects revealed a 29% decrease in PDHB levels, a 47% increase in Pyruvate levels, a 28% increase in Acetyl CoA level, and a 27% increase in Glucose levels. These results supported their initial hypothesis that the pathophysiology of Schizophrenia may be in part due to decreased activity of Glycolysis, and/or the Citric Acid Cycle, resulting in inefficient utilization of glucose in regions of the Central Nervous System such as the striatum. The presence of these metabolic changes in non-MRDS subjects, and their absence in MRDS subjects provides support for their perspective that the individual disorders collectively referred to as schizophrenia may result from completely different biochemical pathways. The authors postulate that changes in glucose metabolism may be protected against by the low levels of CAN Muscarinic Receptors in MRDS subjects, as an explanation for the observed differences between MRDS and non-MRDS subjects.

The results reported in this article provide evidence for a link between inefficient glucose metabolism and non-Muscarinic Receptor Deficit Schizophrenia. However, they do not explain the mechanism that results in such inefficient glucose metabolism. The authors suggest that future research should focus on determining whether the high glucose levels identified in this paper were intracellular or extracellular. In order to go about this, they suggest searching for deficiencies in the quantity of glucose transporters responsible for mediating the uptake of glucose. Such deficiencies would imply that the high glucose levels were extracellular.

While this article may not reveal any findings that have an immediate impact on the treatment of schizophrenia, they open up an entirely new approach by which schizophrenia should be studied. This study is of great importance because it show that to truly understand the biochemistry underlying schizophrenia, the various conditions that fall under this umbrella classification must be studied independently of each other. The notion that the different conditions collectively termed schizophrenia function in entirely different ways has the potential to lead to countless future studies that could explain why current treatments are not effective on all individuals suffering from this disorder.

References:

Dean, B., Thomas, N., Scarr, E., Udawela, M. Evidence for impaired glucose metabolism in the striatum, obtained postmortem, from some subjects with schizophrenia. Transl Psychiatry. 2016, 6(11), 1-9.

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One Reply to “Sometimes the Parts are Greater than the Whole”

  1. Hi Greg, interesting choice of article. Biochemistry is truly present in every field of medicine. With a study such as this one, it is easy to come across many limitations and difficulties. The authors seemed to struggle with the uncertainty in whether glucose uptake and pH (lactate) discrepancies between control and test groups were merely due the tissue being obtained postmortem. It is clear that the authors have gathered enough data to show abnormalities in peripheral glucose metabolism in schizophrenia patients, but for a future study, do you think postmortem can be controlled for in order to obtain more accurate and precise data?

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