Metabolic Changes in Human Brain Evolution and Schizophrenia

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Earlier this year, researchers at the Max Plank Institute for Evolutionary Anthropology, the Shanghai branch of the Chinese Academy of Sciences and Cambridge University published a study in the journal Genome Biology providing further evidence that the evolution of human cognitive abilities was accompanied by adaptive changes in brain metabolism, potentially pushing the human brain to the limit of its metabolic capabilities [1]. The results support the theory that schizophrenia is a consequence of human brain evolution.

Schizophrenia is a disorder known to affect human cognitive abilities, commonly presenting with auditory hallucinations, paranoia and/or disorganized speech and thinking. It is considered a psychosis and is believed to be caused by a combination of genetic and environmental factors. Positron Emission Tomography (PET) brain scans show dramatic differences in the distribution of electrical activity in a normal brain compared to the brain of a schizophrenic patient (right). Schizophrenia affects ~1% of the world’s population with a peak onset in young adulthood; men are more likely to become ill earlier in life than women. Although current treatments can eliminate many of the symptoms of schizophrenia, the molecular causes of the disease have not been identified.

In the present study, researchers compared the molecular changes observed in schizophrenia to changes identified on the human evolutionary lineage and tested whether there was a significant overlap of affected biological processes. Such an overlap would suggest that schizophrenia affects recently evolved biological processes and may provide insights into molecular changes critical for the evolution and maintenance of human-specific cognitive abilities.

The scientists used a published list of 22 biological processes showing evidence of positive (i.e advantageous) selection based on gene expression in the brain during recent human evolution [2]. They then tested whether the expression of genes contained in those biological processes is altered in schizophrenia to a greater extent than expected by chance. Six of the 22 processes were found to be significantly enriched with genes differentially expressed in schizophrenia. Surprisingly, all 6 processes were associated with energy metabolism.

Researchers then studied brain metabolism in human schizophrenia patients and healthy controls, as well as in chimpanzees and rhesus macaques using nuclear magnetic resonance spectroscopy, a method that exploits nuclear magnetic resonance to study molecules. They measured the relative concentrations of 21 metabolites and observed systematic differences, demonstrating that metabolite profiles of the brain appear biochemically distinct among the 4 sample groups. Specifically for schizophrenia, significant differences were observed between schizophrenia patients and controls for 9 of the 21 metabolites. The altered metabolites play key roles in energy metabolism, neurotransmission and lipid/cell membrane metabolism.

Researchers then measured changes in the two metabolite groups (9 metabolites different, 12 metabolites not different) on the human and chimpanzee lineages. Strikingly, phylogenetic analysis showed that the distance between human and chimpanzee for the 9-metabolite group (i.e. metabolites significantly different between schizophrenia patients and controls) is more than three times greater than the 12-metabolite group. This result suggests that schizophrenia affects biological processes changed during human evolution. To further substantiate this result, the scientists measured the extent of amino acid and mRNA expression divergence for genes involved in biological processes related to the 9 metabolites significantly altered between schizophrenia patients and controls. They again found greater divergence between humans and chimpanzees for genes associated with the 9-metabolite group than the 12-metabolite group. Linkage disequilibrium, an indirect but unbiased measure of recent positive selection, further demonstrated that genes associated with metabolites that are altered in schizophrenia and fast evolving on the human lineage display greater amino acid sequence and mRNA expression divergence between humans and chimpanzees that may be due to recent positive selection in humans.

The results suggest that changes in human brain metabolism may have been an important evolutionary step in the development of human cognitive abilities. The findings are consistent with a theory that schizophrenia is a “costly by-product of human brain evolution” [1].

According to lead author Dr. Philipp Khaitovich [3]:

Our brains are unique among all species in their enormous metabolic demand. If we can explain how our brains sustain such a tremendous metabolic flow, we will have a much better chance to understand how the brain works and why it sometimes breaks.

For more information on schizophrenia research, visit the Schizophrenia Research Forum and NARSAD, the world’s leading charity dedicated to mental health research.

To locate mental health and substance abuse treatment services in your area, visit the Substance Abuse and Mental Health Services Administration (SAMHSA) offers a Mental Health Services Locator.

Additional mental health resources are listed in the Highlight HEALTH Web Directory.

References

1. Khaitovich et al. Metabolic changes in schizophrenia and human brain evolution. Genome Biol. 2008;9(8):R124. Epub 2008 Aug 5. DOI: 10.1186/gb-2008-9-8-r124
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2. Khaitovich et al. Positive selection on gene expression in the human brain. Curr Biol. 2006 May 23;16(10):R356-8. Epub 2006 Apr 20.
   View abstract
3. Human brains pay a price for being big. Genome Biology press release. 2008 Aug 1.