Summary: Researchers have identified a brain signaling pathway that can be chemically modulated to reverse autism-related changes in genetically engineered mice. The drug-like intervention normalized both physiology and behavior in adult animals, pointing to a potential path for developing treatments for adults on the autism spectrum.
Source: Florida Atlantic University.
Scientists at Florida Atlantic University have identified a brain-signaling pathway that can be manipulated pharmacologically to reverse autism-related alterations in genetically engineered mice. Using an investigational compound that targets this pathway, the team restored disrupted serotonin transporter function and corrected behavioral and physiological features in adult mice, suggesting a possible avenue for medication development for adults with autism spectrum disorder (ASD).
There are currently no FDA-approved medications that address the core behavioral features of ASD. Published in the Proceedings of the National Academy of Sciences (PNAS), this study describes a novel strategy for targeting an enzyme linked to stress and inflammation to rebalance brain serotonin signaling in a subset of cases that involve serotonin transporter dysfunction.
The research builds on decades of work on serotonin, a neurotransmitter that regulates mood and modulates activity across many brain synapses. Serotonin availability at synapses is tightly controlled by the serotonin transporter (SERT), a protein that clears serotonin from the synaptic space. Small shifts in SERT activity can substantially change serotonin signaling in the brain.
Although altered SERT expression and function have been implicated in several neuropsychiatric conditions, how SERT is regulated in the brain and whether that regulation can be harnessed therapeutically remained unclear.
Randy Blakely, Ph.D., senior author and executive director of FAU’s Brain Institute, first cloned the human SERT gene about 25 years ago and helped show how major antidepressants like Prozac, Zoloft and Lexapro block the transporter. Recognizing the limitations of current medications, Blakely proposed that restoring normal regulatory control of SERT — rather than simply blocking it — could provide a subtler and potentially more effective way to correct serotonin signaling.
“We thought neurons normally adjust transporter activity to keep serotonin levels in balance,” Blakely explained. “We had supporting evidence from cultured cells, but the implications for brain function and disorders were uncertain.”
In 2005, Blakely and collaborators reported several SERT mutations in children with ASD. Notably, these variants made the transporter hyperactive — effectively increasing serotonin clearance beyond normal levels. The most common of these variants, referred to as Ala56, behaves like a transporter stuck in high gear.
Earlier work from Blakely’s lab had identified the enzyme p38α MAPK as a regulator of SERT. Although p38α MAPK is well known for its role in inflammation, multiple studies indicate it also participates in the normal control of serotonin signaling. Changes in molecules downstream of p38α MAPK have been observed in brain tissue from people with ASD, prompting the researchers to test whether excessive p38α MAPK activity was driving SERT hyperactivity in the Ala56 variant.
Using genetic engineering, the team introduced the Ala56 mutation into mice to examine brain biochemistry, neural physiology and behavior. The engineered mice showed p38α MAPK-dependent modifications of SERT, elevated blood serotonin levels (a trait seen in about 25–30 percent of people with ASD), altered hippocampal serotonin clearance, heightened sensitivity of central 5-HT1A and 5-HT2A/2C receptors, repetitive behaviors, communication deficits and reduced social interactions.
These findings suggested the Ala56 mice might serve as a testbed for developing serotonin-targeted therapies. To pursue this idea, the group needed a brain-penetrant, selective inhibitor of p38α MAPK. Biochemist D. Martin Watterson and colleagues developed MW150, a compound with favorable brain uptake and selectivity that had demonstrated safety in animal studies.
“MW150 was critical to our experiments,” said Matthew J. Robson, Ph.D., first author. “Daily dosing for one week reversed many of the biochemical, behavioral and gastrointestinal changes produced by the Ala56 mutation.”
To confirm that these benefits were specifically due to blocking p38α MAPK in serotonin neurons — and not off-target drug effects — the researchers also used conditional gene deletion to remove p38α MAPK selectively from brain serotonin-producing cells. The genetic deletion reproduced the positive effects seen with MW150, strengthening the conclusion that ongoing p38α MAPK activity in serotonin neurons drives the observed abnormalities.
Importantly, the therapeutic effects were seen in adult animals. “Most thinking about ASD treatments focuses on children, but adults with ASD also have substantial unmet needs,” Robson noted. The demonstration that adult brain physiology and behavior can be improved by modulating this pathway opens the possibility of therapies for adults on the spectrum.
ASD is frequently accompanied by medical comorbidities such as gastrointestinal problems. Earlier work by Blakely and collaborators documented impaired enteric nervous system development and reduced gut motility in the SERT Ala56 mice. This study found that MW150 also corrected colonic motility deficits, showing that targeting p38α MAPK can affect both central and peripheral features linked to SERT dysfunction.
The SERT Ala56 variant is relatively uncommon, reported in roughly 1 percent of the U.S. population, and not everyone who carries the variant has ASD. The authors emphasize that the variant likely increases risk only in combination with other genetic or environmental factors. Nevertheless, the work underscores that serotonin’s role in brain disorders extends beyond depression and may identify a subset of patients who could benefit from targeted p38α MAPK inhibition.
Blakely proposes that brain imaging techniques capable of detecting altered SERT levels or serotonin signaling could help identify candidates for such targeted treatments.
Recent prevalence estimates report ASD in approximately 1 in 59 children in the U.S., with a 4:1 male predominance. The lifetime cost of care for an individual with ASD has been estimated in the millions, producing a substantial societal burden.
“Our research has been a long path, and while these results are based on animal studies and more work is required, we remain hopeful that this approach will translate into meaningful therapies beyond the laboratory,” Blakely said.
The research team includes Meagan A. Quinlan, Ph.D.; Paula A. Gajewski-Kurdziel, Ph.D.; Jeremy Veenestra-VanderWeele, Ph.D.; Kara Gross Margolis, M.D.; Michael D. Gershon, M.D.; D. Martin Watterson, Ph.D.; and Randy D. Blakely, Ph.D.
Funding: This study was supported by grants from the National Institutes of Health and the Simons Foundation.
Source: Gisele Galoustian — Florida Atlantic University
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research published in PNAS titled “p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse” by Matthew J. Robson et al., published October 8, 2018.
doi: 10.1073/pnas.1809137115
Florida Atlantic University (2018, October 8). “Pinpointing Pathways that Impact Autism Features.” NeuroscienceNews.
Abstract
p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse
Autism spectrum disorder (ASD) is a common neurobehavioral condition with limited treatment options. Activation of p38 MAPK signaling has been reported in ASD, and p38 MAPK elevates SERT activity — effects that mirror those produced by multiple hyperfunctional SERT coding variants identified in ASD subjects. Mice expressing the SERT Ala56 variant show elevated blood serotonin (hyperserotonemia), p38 MAPK-dependent SERT hyperphosphorylation, increased hippocampal serotonin clearance, altered central 5-HT1A and 5-HT2A/2C receptor sensitivities, and behavioral and gastrointestinal features reminiscent of ASD. Because the α-isoform of p38 MAPK drives SERT activation, researchers tested whether a CNS-penetrant, α-isoform–selective p38 MAPK inhibitor could normalize these phenotypes. One-week treatment of adult SERT Ala56 mice with MW150 restored hippocampal serotonin clearance, receptor sensitivities, social behaviors and colonic motility. Conditional elimination of p38α MAPK from serotonin neurons produced similar improvements, supporting the role of ongoing p38α MAPK activity in driving the physiological and behavioral disturbances in SERT Ala56 mice and suggesting p38α MAPK inhibition as a potential therapeutic strategy for core and comorbid features present in some ASD subjects.