Schizophrenia: Abnormal cyclic gene activity in the brain a factor

  • Researchers at the University of Pittsburgh School of Medicine say they have discovered evidence of 12-hour patterns of gene function in the human brain.
  • The researchers noted that some of these cycles were absent or modified in the brains of people with schizophrenia who had died.
  • While disruptions to 24-hour biological rhythms are common among individuals diagnosed with schizophrenia, little is known about shorter cycles of gene activity in the brain.

In a new study, published in the journal PLOS Biology, researchers are highlighting how individuals diagnosed with schizophrenia commonly experience disruptions in various 24-hour biological rhythms.

These include sleep/wake patterns, hormone secretion, and gene functioning in the prefrontal cortex.

However, scientists still don’t fully understand how genes work in the brain when it comes to cycles shorter than the typical 24-hour sleep-wake cycle.

This is true for both people with schizophrenia and people without the mental health condition.

The new study involved a time-of-death analysis to investigate the gene activity’s 12-hour rhythms within postmortem brains since gene transcript levels can’t be measured in live brains.

Examining the prefrontal cortex for cyclic gene activity

The researchers specifically concentrated on the part of the brain called the dorsolateral prefrontal cortex.

This area of the brain is linked with cognitive symptoms and other irregularities in gene expression rhythms known to occur in schizophrenia.

The team say they discovered several genes in the this area of the brain that exhibit 12-hour patterns of activity.

Specifically, gene activity associated with the creation of connections between neurons was at its highest in the afternoon and evening.

The activity levels of genes linked to mitochondrial function, which is responsible for providing cellular energy, were highest in the morning and evening.

The researchers found that postmortem brains of people with schizophrenia had fewer genes that follow the 12-hour activity cycles and those associated with neural connections were entirely absent.

In addition, although genes connected to mitochondria continued to have a 12-hour rhythm, their activity did not reach its highest point at the usual times.

Circadian rhythms in gene expression and 12-hour cyclic gene activity

The researchers say they discovered that the human brain displays not only circadian (24-hour) rhythms in gene expression but also 12-hour rhythms in several genes that play a critical role in cellular function and neuronal structural maintenance.

People with schizophrenia appear to lose many of these gene expression rhythms and there is a considerable alteration in the timing of rhythms in transcripts related to mitochondria.

This shift in timing could result in suboptimal mitochondrial function when cellular energy is most needed.

Madeline Scott, PhD, a lead study author and researcher at the University of Pittsburgh, explained the key findings to Medical News Today, saying “this study measured gene expression changes over a 24-hour period in the human brain and determined how changes in these patterns are different in people with schizophrenia.”

“In this study we focused on the dorsolateral prefrontal cortex (DLPFC), a brain region important for executive function (the mental processes that enable one to plan, focus attention, remember instructions, and juggle multiple tasks successfully),” she said.

Importantly, we found that genes associated with mitochondrial function (the energy source for cells) had 12-hour rhythms in that their expression peaked twice/day, and that these genes normally peak in expression around 9 a.m. and 9 p.m. In subjects with schizophrenia, while overall we found fewer genes with 12-hour rhythms, genes associated with mitochondria still had 12-hour rhythms but were now peaking in expression at 3 p.m./a.m.

Madeline Scott, University of Pittsburgh

Scott noted that “overall, we believe that these findings suggest that access to energy, through expression of mitochondrial related genes, have a 12-hour rhythm, peaking at ‘transition’ times, when people are likely to be going from sleep to wake, and wake to sleep, when this brain region may need access to the most energy.”

“However, subjects with schizophrenia have suboptimal timing of mitochondrial-related gene expression (~3 PM/AM). This suggests two things: One, they do not have access to energy resources at important times of day for brain function; and two, that energy resources are out of phase with other rhythmic systems, like the immune system,” she added.

Consuelo Walss-Bass, PhD, a professor of psychiatry and behavioral sciences at UTHealth Houston who was not involved in this research, told Medical News Today that “this study used human postmortem brain tissue to investigate alterations in sleep patterns in schizophrenia patients, measured by changes in gene expression at 12-hour periods.”

“This is a very exciting study because it is the first to show alterations in twelve-hour rhythms, which are important for optimal brain function,” Walss-Bass said.

What does this mean for people with schizophrenia?

Scott pointed out that “this specific study shows that individuals with schizophrenia have mistimed and blunted molecular rhythms in a brain region implicated in the cognitive symptoms of the disease.”

There are very few treatments for these symptoms, so further understanding of their biological basis is essential as the field searches for more effective options. Moreover, this research suggests that the daily timing of treatments will be important so that these rhythms can be correctly aligned to appropriate times of day.

Madeline Scott, University of Pittsburgh

Walss-Bass agreed, saying “the importance of maintaining proper sleep patterns for optimal health is now widely acknowledged, and alterations in circadian rhythms in mental health disorders have been previously shown, but this is the first study to show 12-hour rhythm alterations in genes involved in important biological pathways such as energy production and maintenance of brain structure.”

These findings are important for understanding the mechanisms of schizophrenia and could lead to development of novel treatments for this disorder. Overall, the study highlights the importance of utilizing human brain tissue to discover the complex mechanisms underlying schizophrenia.

Consuelo Walss-Bass, UT Health Houston

In the future, further studies need to determine whether these abnormal rhythms are responsible for the behavioral abnormalities associated with schizophrenia, or whether they are caused by medications, nicotine use, or sleep disorders.

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