Study Pinpoints Pathway Impacting Autism Features
Randy Blakely, Ph.D., senior author, executive director of 澳门六合彩历史记录's Brain Institute, and a professor of biomedical science in 澳门六合彩历史记录's Schmidt College of Medicine, and graduate student and co-author Meagan Quinlan.
A team of scientists at has uncovered a brain-signaling pathway that can be pharmacologically manipulated in genetically engineered mice to reverse an autism-related pathway. Using an investigational drug targeting this pathway, the researchers normalized the disrupted physiology and behavior of these mice. Moreover, effects were seen in adult mice, suggesting a possible route to medication development for adults with autism spectrum disorder (ASD). 听
Currently, there are no FDA-approved medications that improve the core symptoms of ASD. Findings from this study, published in the (PNAS), suggest a novel approach to treating this disorder in some people by targeting an enzyme normally associated with stress and inflammation.
The study was based on decades of research by the team on serotonin, a mood-regulating molecule in the brain that regulates many brain synapses 鈥 the gaps between nerve cells where signals are sent and received. The supply of serotonin is tightly regulated by a protein called the serotonin transporter (SERT), which sweeps away serotonin from synapses to limit its action. Shifts in the transporter鈥檚 activity can have significant consequences on the ability of serotonin to act in the brain.
While evidence shows that changes in SERT expression and function may underlie risk for neuropsychiatric disorders, exactly how SERTs are normally regulated in the brain and whether this regulation can be a target for improved medications, and for what disorders, has been unclear.
Randy Blakely, Ph.D., senior author, executive director of 澳门六合彩历史记录鈥檚 , and a professor of in 澳门六合彩历史记录鈥檚 , first identified and cloned the human SERT gene about 25 years ago and established the ability of SERT to be blocked by the major antidepressant medications such as Prozac庐, Zoloft庐 and Lexapro庐. Recognizing the limits of these medications, Blakely hypothesized that resetting the normal regulation of SERT, rather than eliminating its function altogether, might be a more 听subtle and effective way to modify brain serotonin signaling.
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鈥淲e suspected that normally as serotonin signaling changes, neurons turn up or down the activity of this transporter keeping serotonin levels finely balanced,鈥 said Blakely. 鈥淲e generated evidence for this idea using cultured cells that expressed SERT, but what these observations meant for the brain or brain disorders was unclear.鈥
In 2005, Blakely and collaborators at reported multiple mutations in SERT in children with ASD. Remarkably, all of these mutations made the transporter hyperactive all of the time, like an out-of-control vacuum cleaner sucking the air out of a room.
鈥淥ur years of studying SERT gave us a clue as to how to tone down SERT hyperactivity without eliminating the protein鈥檚 normal function,鈥 said Blakely.
A few years before their mutation discovery, Blakely鈥檚 team identified an enzyme, p38伪 MAPK, as a key SERT regulator. This enzyme is well known to be a contributor to inflammatory responses, but work from multiple laboratories suggests that the enzyme plays a role in the normal control of serotonin signaling. Importantly, changes in molecules linked to p38伪 MAPK signaling have been reported in brain samples from ASD subjects. Focusing on the most common of the SERT mutations, Ala56, the group set out to test their theory that SERT was being shoved into 鈥渉igh gear鈥 by the enzyme.
With genetic engineering approaches, the team introduced the Ala56 mutation into the genome of a mouse, where brain biochemistry, physiology and behavior could carefully be examined. As predicted, SERT was found to be modified excessively by p38伪 MAPK. Moreover, they found changes in the behavior of the mice that were reminiscent of some features of ASD. These changes included excessive repetitive behaviors, deficits in communication, and diminished social interactions. In addition, they found elevated serotonin levels in the blood of the mice, a change seen in 25-30 percent of subjects with ASD 鈥 the first time the trait had been reproduced in animals generated to mimic ASD.
鈥淭he studies primarily told us that Ala56 wasn't a benign mutation and possibly that the mice might provide a testbed for developing novel serotoninergic medications,鈥 said Blakely.
To test this idea, Blakely needed a drug that could attack brain p38伪 MAPK potently and specifically. Biochemist , Ph.D., at the at and a co-author, came up with the needed tool known as MW150. 听
鈥淢arty鈥檚 drug was really key to our efforts, as it gets into the brain very well, has good selectivity for p38伪 MAPK, and previously had been demonstrated to be safe to use in animals,鈥 said , Ph.D., first author and an assistant professor in the at the . 鈥淩emarkably, giving the drug once a day for a week reversed many of the changes induced by the SERT Ala56 mutation.鈥 听听听
Encouraged by these findings, yet knowing that drugs can sometimes act on other targets, Blakely鈥檚 team sought another approach to confirm that the drug鈥檚 effects were due to blockade of brain p38伪 MAPK. They decided to eliminate the enzyme only from brain serotonin neurons using a genetic approach called 鈥渃onditional gene deletion.鈥 The effects with animals lacking a functional p38伪 MAPK gene mirrored their findings with MW150. 听听
鈥淎lthough serotonin and SERT are active in the brain throughout development, one key finding of our study is that the effects we saw with MW150 were found in adult mice,鈥 said Robson. 鈥淲hen people think about treating ASD, they generally think about medications for children. While we do not know if our strategy will lead to new medications, treatments that can help adults with ASD is clearly a huge unmet need.鈥 听
The diagnostic features of ASD are behavioral in nature, yet medical comorbidities are common, including bowel problems such as constipation. In 2016, Blakely and a team of researchers at led by Kara Margolis, M.D. and Michael Gershon, M.D., co-authors, demonstrated that in addition to behavioral problems, the SERT Ala56 mice showed poor development of the nerve cells that line the colon and support gut contractions. Astonishingly, Blakely鈥檚 study demonstrated that MW150 also could treat physiological changes linked to gut function in the mice.
鈥淓ven though the first connections between serotonin and ASD were made more than 50 years ago, how we might tap into these observations for potential treatments hasn't been clear,鈥 said Blakely. 鈥淲e think our study suggests a new direction for medication development, particularly if we can identify those patients where changes in brain serotonin make a difference.鈥
The SERT Ala56 mutation is relatively rare and found in only about 1 percent of the U.S. population. Even though Blakely鈥檚 human studies found the DNA change to be associated with traits of ASD, other individuals in the study who carried the variant did not have ASD.
鈥淲e don't think the variant is a cause for ASD in many people; only in those where other genetic or environmental changes have occurred. The bigger message is that serotonin鈥檚 role in brain disorders likely goes far beyond depression,鈥 said Blakely.
Blakely suggests the use of brain-imaging techniques that can scan for changes in SERT levels, or changes in serotonin signaling, could be a possible aid in identifying the right patients for treatment.
Recent estimates indicate a prevalence of ASD in the U.S. of 1 in 59 children with a well-established 4:1 male predominance. Individual costs for care are estimated at about $2.4 million, yielding a societal burden that is expected to exceed $400 billion by 2025.
鈥淚t鈥檚 been a long road with our research efforts,鈥 said Blakely. 鈥淎lthough our studies so far have used mice, and there is still much to do to understand the full significance of the work, I am glad we haven鈥檛 veered from the path. I鈥檓 hopeful that our work will prove meaningful beyond the laboratory.鈥
Study co-authors are Meagan A. Quinlan, Ph.D., 澳门六合彩历史记录鈥檚 Schmidt College of Medicine and Vanderbilt University School of Medicine; Paula A. Gajewski-Kurdziel, Ph.D., 澳门六合彩历史记录鈥檚 Schmidt College of Medicine; and Jeremy Veenestra-VanderWeele, Ph.D., Columbia University College of Physicians and Surgeons.
This research was supported by grants from the National Institutes of Health and the Simons Foundation.
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