Researchers from the RIKEN Brain Science Institute in Japan have shown in mouse models that idiopathic autism could be caused by epigenetic abnormalities in hematopoietic cells during fetal development which resulted in immune dysregulation in the brain and gut.

Led by Toru Takumi, a senior visiting scientist at the RIKEN Center for Biosystems Dynamics Research, the research team used single-cell RNA sequencing to trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism.

In the study published in Molecular Psychiatry on May 2, 2022, researchers showed that in BTBR mice, histone deacetylase 1 (HDAC1) was the cause of immune abnormalities which play an important role in the development of autism spectrum disorder. Brain inflammation and disturbances of the peripheral immune system are frequently observed in autistic patients.

These immune abnormalities were accompanied by abnormalities in the intestinal microbiota, which is also thought to be involved in the pathogenesis of the disease via the brain-gut axis. However, the essential mechanisms behind these immune abnormalities have yet to be fully understood.

A molecular biologist by training, Takumi became interested in neuroscience and wanted to better understand molecular mechanisms in the brain. He started with psychiatric disorders and genetics, and among psychiatric disorders, autism has more genetic causes than schizophrenia or mood disorders, he told BioWorld Science.

Recent contributions in genetic research have identified autism rescue genes, of which there are hundreds, and maybe even thousands, he said.

"We are interested in genome abnormalities, or copy-number variations [CNV], so for our initial study in autism, we generated a mouse model of the CNV."

Given the critical developmental stages of immune insults and the extensive involvement of the immune system in the development of autism, the research team hypothesized that a common etiology underlies the widespread immune dysregulation and originates in different types of progenitor cells.

BTBR mice had different phenotypes in both the brain and the gut, and the researchers looked at earlier stages of the cells.

"We found the change in the HDAC1 activity at a very early stage of brain and blood cell differentiation, and then those differentiated into microglia, and those microglia affect immune status or differentiated into other cells and bone marrow and affect intestinal status and resulted in microbiota changes," Takumi said.

The analysis focused on the hematopoietic cells from which immune cells are derived, as well as on the yolk sac (YS) and the aorta-gonad-mesonephros (AGM), which are involved in hematopoiesis during the fetal stage. These results seek a common ancestor of inflammation in the brain and abnormalities in the peripheral immune system.

During the fetal period, hematopoiesis begins in the YS with primary hematopoiesis and then secondary hematopoiesis occurs in the AGM region. Subsequent hematopoiesis during the fetal period occurs in the liver and lastly in the bone marrow. Hematopoiesis continues throughout a person's life with bone marrow as the main site of this process.

Researchers found that in both AGM and YS progenitors, "the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development," study authors wrote.

"Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain.

"We further confirm that dysregulated immune profiles are associated with specific microbiota composition, which may serve as a biomarker to identify autism of immune-dysregulated subtypes."

Researchers manipulated epigenetic mechanisms during specific developmental stages to restore immune abnormalities in the brain and peripheral tissues.

Regulation of HDAC activity during the fetal stage ameliorated inflammation in the brain and immune dysregulation in BTBR mice, Takumi said.

"HDAC1 inhibitors could be used in pregnancy to see what happens in the immune phenotype. In fact, in the mouse model, the immune phenotype was rescued," he said, noting that many of the mice recovered.

"Environmental causes are also important, especially in maternal immune activation that may stem from maternal infections or stresses that may affect the fetus. Information about the immune system is becoming more critical in understanding these complex diseases," he said.

The findings provide a missing piece to solve the long-time puzzle of systemic immune dysregulation in autism, and it answers some environmental questions about immune adapters, but much remains to be learned about genetic causes.

"Although we know lots of autism risk genes, we don't know how each induvial gene contributes to autism. Environmental factors may contribute more than genetic causes," Takumi said.