Schizophrenic stem cells do not differentiate properly into neurons

November 1, 2016
Representative images of neural differentiation from neurospheres treated with the p38 inhibitor SB203580 (1.0 μM). Neurons and astrocytes were visualized by immunocytochemical staining of βIII-tubulin and glial fibrillary acidic protein (GFAP), respectively. Scale bars, 100 μm. Credit: RIKEN

Researchers at the RIKEN Brain Science Institute have used human-induced pluripotent stem cells (hiPSCs) to identify a characteristic of abnormal brain development in schizophrenia. Published in Translational Psychiatry, the study shows how deletion of a specific gene known to be associated with schizophrenia leads to abnormal differentiation of neurons and an imbalance between the number of neurons and astrocytes in the brain.

While many genetic factors contribute to schizophrenia, small deletions of a region on chromosome 22 are thought to pose a particular risk because several genes at that location are involved in the development and function of in the brain. To investigate exactly how brain development is altered in schizophrenia by genetic deletions in this region, the team led by Takeo Yoshikawa took advantage of modern stem-cell technology. The researchers produced hiPSCs from people without schizophrenia and from patients with schizophrenia who had this deletion, and compared how the different hiPSCs developed into neurons.

Explains Yoshikawa, "When we analyzed the hiPSCs, we found that patient-derived cells differentiated into fewer neurons and greater numbers of astrocytes. We then went further to determine the molecular mechanism underlying these changes in neurogenic and gliogenic competences."

When studying neuron differentiation from , scientists often generate neurospheres—clusters of cells in culture that contain and . The first thing the team noticed was that neurospheres from the patient-derived hiPSCs were on average 30% smaller than normal.

Since the cells in neurospheres can become neurons or glia—another type of brain cell—the team also looked at the proportions of neurons and glia that developed from the different groups of hiPSCs. They found that patient-derived neurospheres differentiated into 10% fewer neurons and about 13% more astrocytes—a type of glial cell—than normal.

The researchers then focused their investigation on the gene DGCR8 because it is located within the special region on chromosome 22, and when deleted in mice, also leads to smaller neurospheres. After confirming that DGCR8 expression was less in patient-derived neurospheres than in the controls, they showed that its deletion was associated with greater expression of the protein p38α, which is known to influence neural/glial competence of stem cells. Inhibition of p38α activity through inhibition of the protein MAPK14 increased the numbers of neurons that developed from patient-derived neurospheres and decreased the numbers of astrocytes.

To determine if this characteristic was true of schizophrenia in vivo, they examined the post-mortem brains of patients who had schizophrenia. They found that the frontal cortex of these brains contains significantly more markers for astrocytes and significantly fewer markers for neurons than the post-mortem brains of people without schizophrenia.

"We ameliorated the lower neurogenic-to-glicogenic competence using a MAPK14 inhibitor", notes Yoshikawa. "These results suggest that MAPK14 inhibitors might be an effective therapy if we could determine the appropriate time for administration, perhaps the early prodromal phase of schizophrenia."

However, Yoshikawa cautions that the molecular mechanisms discovered here may not apply to all cases of schizophrenia. "Our iPS cells from schizophrenia patients are perhaps a special case, because they included the genomic deletion from chromosome 22, which, through MAPK14, led to the imbalance in neuron/astrocyte development. However, there are likely other ways for the same type of imbalance to form in more general cases of ."

Explore further: Study implicates glial cells in fragile X syndrome

More information: Toshima M, Akamatsu W, Okada Y, Ohnishi T, Balan S, Hisano Y, Iwayama Y, Toyota T, Matsumoto T, Itasaka N, Sugiyama S, Tanaka M, Yano M, Dean B, Okano H, Yoshikawa T (2016). Analysis of induced pluripotent stem cells carrying 22q11.2 deletion. Translational Psychiatry. DOI: 10.1038/tp.2016.206

Related Stories

Study implicates glial cells in fragile X syndrome

October 4, 2016
Research on fragile X syndrome, the most common inherited cause of mental retardation, has focused mostly on how the genetic defect alters the functioning of neurons in the brain. A new study focusing on a different type ...

Team discovers neurochemical imbalance in schizophrenia

September 11, 2014
Using human induced pluripotent stem cells (hiPSCs), researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California, San Diego have discovered that neurons from patients with schizophrenia ...

Small molecule keeps new adult neurons from straying, may be tied to schizophrenia

July 6, 2016
A small stretch of ribonucleic acid called microRNA could make the difference between a healthy adult brain and one that's prone to disorders including schizophrenia.

The brain's stunning genomic diversity revealed

September 12, 2016
Our brains contain a surprising diversity of DNA. Even though we are taught that every cell in our body has the same DNA, in fact most cells in the brain have changes to their DNA that make each neuron a little different.

Loss of support cells in brain may inhibit neuronal development

October 7, 2015
Shedding light on possible contributors to autism, schizophrenia and other neuro-psychiatric disorders, researchers have found that a type of support cell abundant in the brain may play a role in the ability of neurons to ...

Zika virus reduces growth and induces cell death and malformations in human neurospheres and brain organoids

April 11, 2016
Brazilian researchers from the D'Or Institute for Research and Education (IDOR) and Federal University of Rio de Janeiro (UFRJ) have demonstrated the harmful effects of ZIKA virus (ZIKV) in human neural stem cells, neurospheres ...

Recommended for you

Mechanism explains how seizures may lead to memory loss

October 16, 2017
Although it's been clear that seizures are linked to memory loss and other cognitive deficits in patients with Alzheimer's disease, how this happens has been puzzling. In a study published in the journal Nature Medicine, ...

Study shows people find well-being more so from special places than from mementoes

October 16, 2017
(Medical Xpress)—A team of researchers at the University of Surrey has found that people experience a feeling of well-being when thinking about or visiting a place that holds special meaning to them. They also found that ...

fMRI scans reveal why pain tolerance goes up during female orgasm and shows brain does not turn off

October 13, 2017
(Medical Xpress)—A team of researchers at Rutgers University has determined why women are able to tolerate more pain during the time leading up to and during orgasm. In their paper published in the Journal of Sexual Medicine, ...

Neuroscientists identify genetic changes in microglia in a mouse model of neurodegeneration and Alzheimer's disease

October 13, 2017
Microglia, immune cells that act as the central nervous system's damage sensors, have recently been implicated in Alzheimer's disease.

Restless legs syndrome study identifies 13 new genetic risk variants

October 13, 2017
A new study into the genetics underlying restless legs syndrome has identified 13 previously-unknown genetic risk variants, while helping inform potential new treatment options for the condition.

Blueberries may improve attention in children following double-blind trial

October 13, 2017
Primary school children could show better attention by consuming flavonoid-rich blueberries, following a study conducted by the University of Reading.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.