A quarterly publication of the Autism Research Institute

The Autism Research Review International is quarterly publication of the Autism Research Institute

Winter, 2020 | Number 1, Volume 34

New study investigates why behavior often improves during fevers for children with ASD

Many parents report that the behavior of children with autism spectrum disorders (ASD) improves when the children have fevers, and a new study by researchers at Harvard and the Massachusetts Institute of Technology offers clues as to why this happens. 

Earlier research by Gloria Choi and Jun Huh found that mice born to mothers that experienced a severe infection during pregnancy were much more likely than other mice to exhibit repetitive behaviors, abnormal communication, and deficits in sociability. The researchers discovered that this was due to exposure to maternal IL-17a, an immune molecule, which produced defects in a brain region called S1DZ in the developing embryos. S1DZ appears to be responsible for sensing where the body is in space. 

In the new study, Choi and Huh, along with lead authors Michael Douglas Reed and Yeong Shin Yim, studied mice that exhibited behavioral symptoms similar to autism due to previous exposure to inflammation during fetal development. The researchers injected the mice with a bacterial component to induce a fever, and found that the social interactions of the animals temporarily became normal. 

The team found that during their fevers, the mice produced IL-17a, which bound to receptors in S1DZ. The immune molecules reduced neural activity in the brain region, making the mice more sociable. When the researchers inhibited IL-17a or knocked out the receptors for it, this increased sociability did not occur. In addition, simply raising the body temperature of the mice had no effect on behavior. 

“This suggests that the immune system uses molecules like IL-17a to directly talk to the brain,” Choi says, “and it can actually work almost like a neuromodulator to bring about these behavioral changes.” 

Dan Littman, a professor of immunology who was not involved in the study, commented, “What’s remarkable about this paper is that it shows that this effect on behavior is not necessarily a result of fever but the result of cytokines [immunoregulatory proteins] being made. There’s a growing body of evidence that the central nervous system, in mammals at least, has evolved to be dependent to some degree on cytokine signaling at various times during development or postnatally.” 

The researchers performed the same experiments on three different genetic mouse models of autism (mice lacking Shank3, Cntnap2, or Fmr1), but giving these mice fevers did not stimulate IL-17a production and did not alter their behavior. However, when the researchers injected the genetically modified mice with IL-17a, their behavior did improve. Reed and colleagues say this suggests that mice exposed to inflammation during gestation develop immune systems that are primed to more readily produce IL17a during subsequent infections. 

Huh comments, “It was amazing to discover that the same immune molecule, IL17a, could have dramatically opposite effects depending on context: promoting autism-like behaviors when it acts on the developing fetal brain and ameliorating autism-like behaviors when it modulates neural activity in the adult mouse brain.” 

In separate research, Choi and Huh found that presence of certain bacteria in the gut can also prime IL-17a responses. The researchers are now investigating whether gut bacteria play a role in the fever-induced reversal of social impairments that they detected in their study.

The team found that during their fevers, the mice produced IL-17a, which bound to receptors in S1DZ. The immune molecules reduced neural activity in the brain region, making the mice more sociable. When the researchers inhibited IL-17a or knocked out the receptors for it, this increased sociability did not occur.

Citations

“IL-17a promotes sociability in mouse models of neurodevelopmental disorders,” Michael Douglas Reed, Yeong Shin Yim, Ralf D. Wimmer, Hyunju Kim, Changhyeon Ryu, Gwyneth Margaret Welch, Matias Andina, Hunter Oren King, Ari Waisman, Michael M. Halassa, Jun R. Huh, and Gloria B. Choi, Nature, December 18, 2019 (online). Address: Jun Huh, [email protected]

—and— 

“Study may explain how infections reduce autism symptoms,” news release, Anne Trafton, Massachusetts Institute of Technology, December 19, 2019.