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Immune cells in the brain may be possible new targets for treating ASD and intellectual disability, preclinical study suggests – ScienceDaily


Scientists at the University of Buffalo have discovered a convergent mechanism that may account for how two high-ranking genetic risk factors for autism spectrum disorders/intellectual disability (ASD/ID) lead to these neurodevelopmental disorders.

While ASD is distinct from ID, a significant proportion—about 31%—of people with ASD also exhibit ID. Neither condition is well understood at the molecular level.

“Given the huge number of genes known to be involved in ASD/ID and the many potential mechanisms that contribute to the disorder, it is very exciting to find a common process between two different genes at the molecular level that may underlie behavioral changes,” said Megan Conrow-Graham, PhD, is first author and MD/PhD candidate in the Jacobs School of Medicine and Biomedical Sciences at University College.

Published today in the magazine The brain, the article focuses on ADNP and POGZ, the two highest ranked ASD/ID risk factor genes. The research shows that mutations in these genes lead to abnormal activation and overexpression of immune response genes and genes of a type of immune cell in the brain called microglia.

“Our finding opens up the possibility of targeting microglia and immune genes for the treatment of ASD/ID, but much remains to be learned given the heterogeneity and complexity of these brain disorders,” said Zhen Yan, Ph.D., senior author and SUNY Professor Emeritus in the Department of Physiology and Biophysics at the Jacobs School.

UB scientists found that mutations in two studied genes activate microglia and cause overexpression of immune genes in the brain. The hypothesized result is the abnormal function of synapses in the brain that is characteristic of ASD/ID.

The research included studies of post-mortem brain tissue from people with ASD/ID, as well as studies in mice in which ADNP and POGZ were silenced via viral delivery of small interfering RNA. These mice showed impairments in cognitive tasks such as spatial memory, object recognition memory, and long-term memory.

Weakening of the repressive function

“Under normal conditions, cells of the central nervous system should not express a large number of genes that activate the immune system,” Conrow-Graham said. “ADNP and POGZ work to suppress these genes so that inflammatory pathways are not continuously activated, which can damage surrounding cells. When this suppression is relaxed, these immune and inflammatory genes can be expressed in large amounts.’

Upregulation of genes in the prefrontal cortex of mice induced by ADNP or POGZ deficiency activated a proinflammatory response.

“This is consistent with what we see in genes upregulated in the prefrontal cortex of people with ASD/ID,” Conrow-Graham said. The prefrontal cortex is the part of the brain responsible for executive functions such as cognition and emotional control.

The mutated genes also activate glial cells in the brain, called microglia, which serve as support cells for neurons and perform an immune function in the brain; they make up 10-15% of all brain cells.

Sensitive microglia

“Microglia are highly sensitive to pathological changes in the central nervous system and are the primary form of active immune defense to maintain brain health,” Yang explained. “Aberrant activation of microglia, which we demonstrate occurs as a result of ADNP or POGZ deficiency, can lead to damage and loss of synapses and neurons.”

The researchers hope that future studies will determine whether chronic neuroinflammation may directly contribute to at least some cases of ASD/ID, in which targeting microglia or inflammatory signaling pathways may prove to be a useful treatment.

The researchers noted that the clinical manifestations of both ASD and ID are incredibly diverse. Substantial variation is also likely to be present in the types of mechanisms responsible for the symptoms of ASD and/or ID.

“We found that changes in two risk genes lead to a convergent mechanism, likely involving immune activation,” Conrow-Graham said. “However, this is probably not the case for all people with ASD/ID. When designing clinical trials to evaluate the effectiveness of treatments, I think our study highlights the importance of considering the genetic factors associated with ASD/ID in humans.”

The research is the culmination of Conrow-Graham’s PhD thesis; now she has returned to complete the final two years of her MD at the Jacobs School. She described her experiences with the MD and PhD degrees as extremely complementary.

The immune system has a role

“My training at each level was extremely useful to complement the other,” she said. “When I started my doctoral work, I did two years of MD training, so I was familiar with the basics of physiology, anatomy and pathology. Because of this, I was able to bring a broader perspective to my neuroscience research, identifying how the immune system could play a role. Prior to this, our lab had not investigated pathways related to immunology, so having this understanding was very helpful.”

She added that she learned a lot from all of her colleagues in Jan’s lab, including faculty, lab assistants, and other students. “I learned a lot of technical skills that I never used before I came to the lab because of the dedication of my lab colleagues to my training,” she said.

Her experiences working at the lab bench on the basic science underlying neuropsychiatric disorders will certainly influence her work as a clinician.

“I plan to pursue a career as a child and adolescent psychiatrist, so I may be able to work directly with this patient population,” she said. “We are now learning that the best care can be provided through an individualized approach to medicine that takes into account genetics, psychosocial factors and more. The opportunity to dive very deeply into the field of psychiatric genetics has been a privilege. I hope it will help me provide better patient care.”

The research was funded by the Nancy Lurie Marks Family Foundation and the Ruth L. Kirschstein National Institutes of Health.

In addition to Conrow-Graham and Yan, co-authors include Jamal B. Williams, Ph.D., former graduate student; Jennifer Martin, Ph.D., former doctoral student; Ping Zhong, Ph.D., Senior Research Fellow; Qing Cao, Ph.D., PhD student; and Benjamin Raine, Ph.D., former graduate student.

All are current or former members of Ian’s lab.

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