Schizophrenia: It’s All Connected!

Schizophrenia is a psychiatric disease characterized by the experience of positive and negative symptoms. Positive symptoms refer to those such as delusions (firm beliefs that are contrary to reality), disorganized speech and behavior, and hallucinations (hearing, seeing, tasting, or smelling things that are not there). Negative symptoms are deficiencies in normal emotional displays, while cognitive symptoms affect functions such as memory. The disease has been a hot topic in research, as only 13.5% of patients recover.

Studies have illuminated a couple of hypotheses as to how Schizophrenia works. Two hypotheses implicate abnormalities in neurotransmission. This refers to the process governing function of the nervous system by which specialized cells called neurons transfer information by releasing signaling molecules called neurotransmitters, that attach to specific receptor proteins on adjacent neurons. Research has indicated that impairments in glutamate neurotransmission, a primary system in the human brain which uses glutamate as a neurotransmitter, could be responsible for the symptoms of Schizophrenia.

Another hypothesis implicates abnormal glucose metabolism as a source of the symptoms. To perform their biological function, cells require energy, which is produced by the breakdown of sugars (glucose), fats, and proteins. Neurons are known to have the highest energy requirement of any cell type, thus low energy production could have severe consequences. Glucose breakdown occurs first by glycolysis which makes 2 pyruvate molecules from each glucose molecule. Pyruvate is converted to Acetyl-CoA which then enters a series of reactions called the TCA Cycle (Fig 1).

These two hypotheses may be interconnected, as glutamate is made from molecules formed in the TCA Cycle. Various studies have found low activity and concentrations of TCA enzymes and metabolites, respectively, in the Schizophrenic Brain. Many of these can be directly linked to glutamate production (Fig. 1). Studies have also shown that blocking glutamate neurotransmission can produce the symptoms of schizophrenia in healthy individuals. Because low glutamate levels would have the same effect, impaired glucose metabolism could be directly responsible for observed impairments in neurotransmission. Therefore, supplementing TCA cycle enzymes to improve activity, or administration of specific TCA Cycle metabolites could be viable options for treatment.

 

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