Abnormalities in the tricarboxylic acid (TCA) cycle in the brains of schizophrenia patients

Abstract

Images of brain metabolism and measurements of activities of components of the electron transport chain support earlier studies that suggest that brain glucose oxidation is inherently abnormal in a significant proportion of persons with schizophrenia. Therefore, we measured the activities of enzymes of the tricarboxylic (TCA) cycle in dorsolateral-prefrontal-cortex from schizophrenia patients (N=13) and non-psychiatric disease controls (N=13): the pyruvate dehydrogenase complex (PDHC), citrate synthase (CS), aconitase, isocitrate dehydrogenase (ICDH), the alpha-ketoglutarate dehydrogenase complex (KGDHC), succinate thiokinase (STH), succinate dehydrogenase (SDH), fumarase and malate dehydrogenase (MDH). Activities of aconitase (18.4%, p<0.05), KGDHC (26%) and STH (28.2%, p<0.05), enzymes in the first half of the TCA cycle, were lower, but SDH (18.3%, p<0.05) and MDH (34%, p<0.005), enzymes in the second half, were higher than controls. PDHC, CS, ICDH and fumarase activities were unchanged. There were no significant correlations between enzymes of TCA cycle and cognitive function, age or choline acetyl transferase activity, except for aconitase activity which decreased slightly with age (r=0.55, p=003). The increased activities of dehydrogenases in the second half of the TCA cycle may reflect a compensatory response to reduced activities of enzymes in the first half. Such alterations in the components of TCA cycle are adequate to alter the rate of brain metabolism. These results are consistent with the imaging studies of hypometabolism in schizophrenia. They suggest that deficiencies in mitochondrial enzymes can be associated with mental disease that takes the form of schizophrenia.

Figure 1

TCA Cycle

Figure 2

Comparison of TCA cycle enzymes in the brains of humans and mice Values are Means ± SEM N1=13, N2=6

Figure 3

Post-Mortem stability of TCA cycle enzyme activities in mice brain. Values (Means ± SEM) are specific activities (nmole/min per mg protein). ¹CS activity was estimated by coupled assay. *p<0.05 **p<0.005 NIH Swiss mice (Harlan Sprague Dawley Indianpolis, IN) were used. Twenty-four mice were divided into four equal groups. All the mice in four groups were killed by cervical dislocation and kept at 4 degrees for 0 minute, 3 hours, 6 hours and 12 hours.

Figure 4

Changes in the activities of TCA cycle enzymes in brains of schizophrenia patients in comparison to controls *p<0.05, **p<0.005, % Change = (Control Mean-Values)/Control Mean *100 N1=N2=13