Abnormal 12-Hour Cyclic Gene Activity Found in Schizophrenic Brains

Fewer 12-hour rhythmic genes were present and many of those that remained showed a peak at an incorrect time.

The researchers at the University of Pittsburgh School of Medicine in the United States have presented the first proof of 12-hour cycles of gene activity in the human brain. The study, led by Madeline R. Scott, was published in the journal PLOS Biology and also discovered that some of these 12-hour rhythms are absent or altered in the postmortem brains of patients with schizophrenia.

It is well established that individuals with schizophrenia experience disruptions in various 24-hour bodily rhythms, including their sleep-wake patterns, hormone levels, and gene activity in the prefrontal cortex of the brain. However, there is limited understanding of gene activity in the brain, both in healthy individuals and those with schizophrenia, for rhythms that are shorter than the typical 24-hour circadian rhythm.

Because gene transcript levels cannot be measured in living brains, the new study used a time-of-death analysis to search for 12-hour rhythms in gene activity within postmortem brains. They focused on the dorsolateral prefrontal cortex because this region of the brain is associated with cognitive symptoms and other abnormalities in gene expression rhythms that have been observed in schizophrenia.

The researchers found numerous genes in the normal dorsolateral prefrontal cortex that have 12-hour rhythms in activity. Among them, gene activity levels related to building connections between neurons peaked in the afternoon/night, while those related to mitochondrial function (and therefore cellular energy supply) peaked in the morning/evening.

In contrast, postmortem brains from patients with schizophrenia contained fewer genes with 12-hour activity cycles, and those related to neural connections were missing entirely. Additionally, although the mitochondria-related genes did maintain a 12-hour rhythm, their activity did not peak at the normal times. Whether these abnormal rhythms underlie the behavioral abnormalities in schizophrenia, or whether they result from medications, nicotine use, or sleep disturbances should be examined in future studies.

Coauthor Colleen A. McClung adds, “We find that the human brain has not only circadian (24-hour) rhythms in gene expression but also 12-hour rhythms in a number of genes that are important for cellular function and neuronal maintenance. Many of these gene expression rhythms are lost in people with schizophrenia, and there is a dramatic shift in the timing of rhythms in mitochondrial-related transcripts which could lead to suboptimal mitochondrial function at the times of day when cellular energy is needed the most.”

Reference: “Twelve-hour rhythms in transcript expression within the human dorsolateral prefrontal cortex are altered in schizophrenia” by Madeline R. Scott, Wei Zong, Kyle D. Ketchesin, Marianne L. Seney, George C. Tseng, Bokai Zhu and Colleen A. McClung, 24 January 2023, PLOS Biology.
DOI: 10.1371/journal.pbio.3001688