MITOCHONDRIAL INVOLVEMENT IN SCHIZOPHRENIA AND OTHER FUNCTIONAL PSYCHOSES

Gene expression has been studied in post-mortem frontal cortex samples from patients who had suffered from schizophrenia and depressive illn ess. mRNA was extracted and characterised by translation and separatio n of the products by 2D gel electrophoresis. Post-mortem artefacts and the agonal experience did not affect the size distribution or amount of specific translation products. Four expression products were specif ically reduced in samples from schizophrenics compared with normals. T he expression of six products was altered in affective disorder, one i n common with schizophrenia, two the same as in schizophrenia but incr eased. cDNA libraries were produced from the mRNA samples and 5 clones present at abnormal levels in schizophrenia identified by differentia l screening, isolated and sequenced. All the sequences encode mitochon drial transcripts; four encode mitochondrial rRNA and one the amino ac id sequence of cytochrome oxidase sub-unit II. Increased cytochrome ox idase transcripts were found in a further set of mRNA extracts from sc hizophrenic patients including two who had not received neuroleptic me dication. The effects of neuroleptic administration as exemplified by ol-flupenthixol compared with the ineffective P-flupenthixol were stud ied in experimental animals. It was found that 13 out of 28 clones who se levels were altered were mitochondrial in origin including rRNA, CO X I & II and the NADH-Q reductase. Those encoding respiratory enzymes were at abnormally low levels as a result of ol-flupenthixol administr ation. Measurements of the enzymic activity of cytochrome c oxidase in post-mortem frontal cortex of schizophrenics did not indicate any dif ferences in overall activity but there was a decreased sensitivity to azide that was abolished by neuroleptics. Studies on NADH-cytochrome c reductase showed that schizophrenics whether medicated or not had a r educed rotenone sensitive activity that was compensated for by increas ed rotenone insensitive activity. We conclude that changes in mitochon drial gene expression are involved in schizophrenia and probably other functional psychoses.