Tokai University reveals causative gene in autism spectrum disorder functions in immune cells in the brain

A research team led by Visiting Professor Tomoko (Ishino) Kaneko at Tokai University School of Medicine, and Adjunct Lecturer Fumitoshi Ishino at the Research Infrastructure Management Center of the Institute of Science Tokyo (professor emeritus at the Institute of Science Tokyo), has revealed that retrotransposon Gag-like 4 (RTL4), a gene thought to be responsible for autism spectrum disorder (ASD), is expressed in microglia, which are immune cells in the brain, and is increased in response to noradrenaline (NA), which plays an important role in arousal, attention, and adaptation to novel environments. The study was published in the International Journal of Molecular Sciences.

In 2015, the research group reported that mice lacking RTL4, a mammalian-specific gene derived from a virus, exhibit increased impulsivity, decreased adaptation to novel environments, reduced short-term spatial memory, and delayed NA recovery in the brain's prefrontal cortex. Mutations in the RTL4 gene are found in patients with ASD, albeit infrequently, and RTL4 is considered to be one of the causative genes in ASD. However, its actual function in the brain has long been unknown because its expression is extremely low.

In this study, with the support of Assistant Professor Yuichi Hiraoka and Assistant Professor Toru Suzuki of the Laboratory of Genome Editing for Biomedical Research, Medical Research Institute, Institute of Science Tokyo, the research group created knock-in (KI) mice carrying a fusion gene in which the RTL4 gene was followed by a gene encoding the fluorescent protein Venus. They analyzed the expression sites and dynamics of the synthesized RTL4CV protein in the brain in detail. Observations using a confocal laser microscope with the ability to computationally extract only the fluorescence of Venus confirmed that the RTL4CV protein was expressed in the hypothalamus, midbrain, amygdala, and hippocampus of the postnatal brain. Other findings included that the RTL4CV signal intensity increased when KI mice were exposed to various stimuli (e.g., smell, sound, and brightness) or underwent the administration of isoproterenol, which mimics the function of NA and that RTL4CV was specifically expressed in microglia, which are the immune cells in the brain.

While microglia have been implicated in a variety of psychiatric disorders, this is the first study to demonstrate that a microglia-specific gene is involved in the development of ASD.

The RTL4 protein, which is responsive to NA, was found to be secreted from microglia during postnatal adaptation to novel environments. For example, newborns recognize the maternal odor during this period. Demonstrating the brain dynamics of the RTL4 protein leading to the development of ASD is a major step toward elucidating the pathogenesis of the disease. It may contribute to the development of new therapeutic agents.

The involvement of a gene based on DNA from ancient retrovirus infection in important brain functions related to the development of ASD suggests that viruses played major roles in the evolution of mammals, including humans. While genes account for only 1.5% of the human genome, endogenous retroviruses such as RTL/SIRH genes account for 9%. Although these have not been studied for a long time, the present study suggests the possibility of existence of many unknown retrovirus-derived genes, some of which might have been involved in human evolution.

Journal Information
Publication: International Journal of Molecular Sciences
Title: RTL4, a Retrovirus-Derived Gene Implicated in Autism Spectrum Disorder, Is a Microglial Gene That Responds to Noradrenaline in the Postnatal Brain
DOI: 10.3390/ijms252413738