In Schizophrenia, Differences in the Brain’s Energy Pathways Suggest Possible New Treatment Target

In Schizophrenia, Differences in the Brain’s Energy Pathways Suggest Possible New Treatment Target

Posted: February 18, 2021
In Schizophrenia, Differences in the Brain’s Energy Pathways Suggest Possible New Treatment Target

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Researchers using a variety of schizophrenia datasets have discovered differences in the way subjects’ brain cells generate and use energy. The findings shed light on potential causes of brain pathologies that underlie schizophrenia and point to a new potential treatment target.


It has long been known that schizophrenia and bipolar disorder share certain risk factors as well as clinical features. For instance, some of the same genetic variations that occur in both illnesses rarely or never occur in unaffected individuals. Psychosis—having delusions, hallucinations, or difficulty distinguishing what is and is not real—can affect people with either diagnosis.

These and other features shared by the two illnesses may or may not have common biological causes; the extent to which this is true has been a subject of much research in recent years. In the American Journal of Psychiatry, a team led by 2015 BBRF Young Investigator Jill R. Glausier, Ph.D. and 2008 BBRF Distinguished Investigator David A. Lewis, M.D., both of the University of Pittsburgh, has reported on their efforts to discover whether dysfunctions in the way cells generate and use energy can shed light on similarities between schizophrenia and bipolar disorder.

The study focused on mitochondria—the tiny energy factories found in abundance within nearly all of our cells. Evidence from past research has indicated that mitochondrial function appears to be different in people with the two illnesses, compared with people who don’t have either illness. Additionally, there is evidence that in both illnesses, a variety of processes which depend upon the energy that mitochondria generate, and the biological pathways that are involved in generating and conveying the energy, may be perturbed, perhaps in similar ways.

The researchers used a variety of datasets collected from individuals with schizophrenia, bipolar disorder, and unaffected subjects who donated their brains for scientific research. These datasets revealed patterns of gene expression in a region of the brain called the dorsolateral prefrontal cortex (DLPFC). Data from all DLPFC cells, or in some subjects specifically from excitatory (pyramidal) neurons in two layers of the DLPFC, called layer 3 and layer 5, were investigated.

The most important finding of the analysis was that mitochondria-related genes in these brain cells were much more often expressed (i.e., activated or “switched on”) in a different pattern in subjects with schizophrenia (41% of such genes) than in subjects with bipolar disorder (8%), compared with such patterns in unaffected subjects.

Further, 83% of the genes that were expressed differently among the subjects with schizophrenia were “downregulated,” a term meaning that they had lower levels of activation compared with the same genes in unaffected people. Nearly all of these downregulated genes are important for regulating mitochondrial energy production. This lower expression level has multiple impacts on other biological processes, some involving mitochondria directly, and others affecting cells and processes in the brain that depend on the energy that mitochondria generate.

These findings, the researchers suggest, in turn shed light on various theories about potential causes of brain pathology that underlie schizophrenia. They also point to a new potential treatment target for schizophrenia.

It has been noted in large surveys of affected vs. unaffected people that genetic variations commonly seen in schizophrenia often affect various aspects of synapses, the tiny gaps across which neighboring neurons communicate. The affected genes have been linked, among other things, to the formation of synapses, the process of communicating across synapses, and the formation and operation of tiny pores in neurons which regulate charged molecules that affect whether and when they will “fire.”

Biological evidence of neuronal “hypofunction” (lower firing rates) has been reported in schizophrenia. The downregulation of mitochondrial genes in schizophrenia noted in the study by Drs. Glausier, Lewis and colleagues is consistent with this evidence, as it suggests lower amounts of energy generated by brain cells in order to build and communicate across synapses. This may be the result of lower demand by cells which communicate less than normal, rather than defects in mitochondria themselves, the researchers point out.

As noted in an editorial commentary accompanying the paper in the American Journal of Psychiatry, mitochondrial pathology thus “could be an important factor in the manifestation of clinical symptoms” in the illness.

While these are only a few among the many findings of the study, they point to the possible utility of future therapies which might seek to increase firing rates in excitatory neurons in affected areas of the brain in people diagnosed with schizophrenia.

The researchers were careful to note that the high rate of differential expression seen in mitochondria-related genes in schizophrenia vs. bipolar disorder does not mean that mitochondrial function is not perturbed in the latter illness. Mitochondrial dysfunction in bipolar disorder may be manifest in other brain areas or cell types, or may affect different processes, suggesting an important aspect of brain biology that may distinguish pathologies in bipolar disorder and schizophrenia.