Mitochondrial Function is Differentially Altered in the Basal Ganglia of Chronic Schizophrenics

Abstract

In the present study, we have applied a novel strategy involving the postmortem measurement of the mitochondrial respiratory chain enzyme cytochrome-c oxidase (COX; complex IV) to identify regional changes in energy metabolism in the basal ganglia of chronic, medicated schizophrenics. COX activity was decreased in the caudate nucleus but increased in the putamen and nucleus accumbens. An increase in succinate dehydrogenase (complex II) was evident in the putamen and nucleus accumbens, but changes were not seen with NADH dehydrogenase (complex I). An analysis of interregional correlations in energy metabolismThe main contributors to the search for functional brain changes in schizophrenia have employed imaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) to identify potential candidate regions which may define disease symptomatology. To date, over 300 published articles exist (Medline database 1966(Medline database -1997 in which imaging techniques have been utilized in schizophrenics. While the power of PET as a tool for understanding 'statedependent' brain function and receptor characteristics, as well as offering excellent patient control, is generally undisputed, the sheer bulk of data created by researchers in the field has generated a disconcertingly diffuse base of evidence for which regions may be involved in the disease. Although a general trend implicating reduced metabolism in cortical and sub-cortical regions has formed the foundation for assumptions about a possible defect in schizophrenics (Buchsbaum et al. 1982(Buchsbaum et al. , 1992Tamminga et al. 1992;Siegel et al. 1993), opposite findings have been made (Early et al. 1987;Wiesel et al. 1987;Cleghorn et al. 1989).As a complement to imaging studies, our laboratory has applied a strategy involving the post-mortem measurement of the mitochondrial respiratory chain en- COX Activity and Schizophrenia 373 zyme cytochrome-c oxidase (COX) in an attempt to localize altered brain function in schizophrenia. This approach is based upon a strong body of evidence which indicates that neuronal COX is highly regulated by the energy demands of the cell and as such represents an endogenous marker of cellular energy metabolism over time (Wong-Riley 1989). Interest in COX as a marker of neuronal function rests upon many of the same assumptions implicit in the use of PET in the measurement of regional glucose metabolism and blood flow. Neurons are highly dependent upon oxidative phosphorylation as the primary pathway for the generation of ATP, of which 40-60 % is utilized in the maintenance of ion gradients by ATPases. In support of this, a strong correlation has been demonstrated between the regulation of COX and Na ϩ ,K ϩ ATPase in brain tissue (Hevner et al. 1992). Traditionally however, the strongest evidence that COX is coupled to neuronal energy demands comes from studies in which changes in COX activity can be induced by experimental interventions which alter n...

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

“…[31][32][33][85][86][87][88] The results of this study extend this abnormality to bipolar disorder, whereby almost half of all significantly differentially expressed proteins identified were found to have a mitochondrial or other metabolic function. In the schizophrenia group, this figure was a quarter, suggesting that metabolic dysfunction in this area is relatively more prominent in bipolar disorder than schizophrenia.…”

Comprehensive expression analysis of a rat depression model

“…These findings may highlight region-specific molecular mechanisms involved in the etiology of LH. In human studies, decreased mitochondrial function was demonstrated in the basal ganglia of chronic schizophrenics, 47,48 and inhibition of mitochondrial respiratory complex I activity was reported as a cellular pathology of Parkinson's disease. 49,50 Evidence, including that of decreased ATP in frontal lobes detected in depressive patients, 51 has generated speculation about the role of mitochondrial dysfunction in depression.…”

State-dependent alterations in mitochondrial complex I activity in platelets: a potential peripheral marker for schizophrenia

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