Guilt by dissociation: Study sheds light on serotonin in autism

Recent estimates indicate a prevalence of autism spectrum disorder (ASD) in the United States 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. Currently, there are no FDA-approved medications that improve the core symptoms of ASD.

Neuroscientists in the laboratory of Randy D. Blakely, Ph.D., professor of biomedical science in Florida Atlantic University’s Schmidt College of Medicine and executive director of the FAU Brain Institute, are focused on serotonin, a mood-regulating molecule in the brain that regulates many brain synapses — 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’s activity can significantly impact the ability of serotonin to act in the brain.

Changes in signaling by the neurotransmitter serotonin has been connected to autism for more than 50 years, dating back to findings of elevated serotonin levels in the blood of some people with the disorder, a feature termed hyperserotonemia. Since this time, multiple rare changes in the genetic code that impact SERT have been observed.

Recent studies of mice expressing the most common of these gene variants, called SERT Ala56, induces behavioral changes in animals that scientists connect to alterations in people with autism – repetitive behavior, altered communication, and atypical social interactions, as well as hyperserotonemia. Although the effects of the SERT Ala56 mutation are paralleled by other mutations in the SERT gene, none of these mutations are common enough to account for the number of individuals with autism demonstrating hyperserotonemia.

Blakely and collaborators have published a study in the journal Frontiers in Molecular Neuroscience, which now offers a possible explanation for this puzzle.

“We have known for some time that the activity and regulation of the SERT protein is critically dependent on a number of other proteins that tell the protein where to locate on nerve cells and how to act,” said Blakely, lead author.

It turns out that the SERT Ala56 mutation changes the structure of the transporter in ways that keep these partner proteins from interacting with the transporter, a protein that Blakely’s laboratory identified thirty years ago.

Last year, Blakely’s former graduate student Meagan Quinlan, Ph.D., first author and a post-doctoral fellow at the University of Washington, demonstrated that the SERT Ala56 mutation impacts the structure of the SERT protein in cells in culture, revving up the transporter into a state of abnormally high activity.

“We think that this high-activity state results in removal of too much serotonin from sites in the brain where serotonin is needed, both during development and in adults,” said Quinlan. “I suspect that the structural changes we have observed likely reflected changes in the regulatory ability of SERT-associated proteins to maintain serotonin inactivation at normal levels.”

To test this concept, Quinlan purified the mutant transporter from the brain of SERT Ala56 expressing mice, as well as from normal mice, and then determined whether proteins normally bound to SERT were still attached.

“We found that only a few proteins seemed to interact with SERT Ala56 more than they should. In contrast, many more proteins appeared no longer tethered to the transporter, including some proteins we already knew to be SERT regulators and others that have been linked to ASD,” said Quinlan.

Blakely was actually quite surprised at the findings. “It is quite amazing that one of the smallest changes you can make in SERT can alter its interactions with partners,” said Blakely.

According to Blakely, further work could reveal more extensive links between SERT and other genes known to associate with autism, broadening the impact of SERT Ala56 to other neurotransmitter systems.

“Following the scent of serotonin may well take us to molecules and medications we had no clue about just a few years ago,” said Blakely.

Blakely’s team recently reported a new small molecule that can tone down SERT activity and normalize behaviors in the SERT Ala56 mouse, a molecule that he hopes may lead to a new therapeutic.

“A goal moving forward with this drug is to see if it can reverse the changes in SERT Ala56 protein associations, tying the molecular changes we see with the mutant to how the drug may work,” said Blakely.

ASD is a serious developmental disorder with increased prevalence that impairs the ability to communicate and interact and impacts the nervous system. The range and severity of symptoms can vary widely and common symptoms can include difficulty with communication and social interactions, obsessive interests, and repetitive behaviors. No current medications treat the core features of ASD.

###

Study co-authors are Matthew J. Robson, Ph.D., Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati; Ran Ye, Ph.D., Department of Pharmacology, Vanderbilt University; and Kristie L. Rose, Ph.D., and Kevin L. Schey, Ph.D., both within the Department of Biochemistry, Vanderbilt University.

Financial support for the studies derives from Vanderbilt Pharmacology T32 (GM07628), an Elaine Sanders-Bush Scholar’s Award from the Vanderbilt Silvio O. Conte Center for Neuroscience Research (Quinlan), Vanderbilt Digestive Disease Research Center (P30DK058404), PhRMA Foundation Award and NARSAD YI Award 25230 (Robson), and National Institutes of Health grants MH096972 (Blakely) and MH094527 (Blakely).

FAU’s Charles E. Schmidt College of Medicine is one of approximately 155 accredited medical schools in the U.S. The college was launched in 2010, when the Florida Board of Governors made a landmark decision authorizing FAU to award the M.D. degree. After receiving approval from the Florida legislature and the governor, it became the 134th allopathic medical school in North America. With more than 70 full and part-time faculty and more than 1,300 affiliate faculty, the college matriculates 64 medical students each year and has been nationally recognized for its innovative curriculum. To further FAU’s commitment to increase much needed medical residency positions in Palm Beach County and to ensure that the region will continue to have an adequate and well-trained physician workforce, the FAU Charles E. Schmidt College of Medicine Consortium for Graduate Medical Education (GME) was formed in fall 2011 with five leading hospitals in Palm Beach County. The Consortium currently has five Accreditation Council for Graduate Medical Education (ACGME) accredited residencies including internal medicine, surgery, emergency medicine, psychiatry, and neurology.

Inaugurated in 2016 on the John D. MacArthur Campus in Jupiter, Fla., the FAU Brain Institute, supports research, education and community outreach among more than 100 faculty level researchers at FAU and its affiliate research centers. One of FAU’s four pillars that guide the University’s goals and strategic actions, the Institute seeks to unlock the secrets of brain development, function and plasticity and how the mechanisms uncovered can be compromised to drive devastating brain disorders. From the study of neuronal development and signaling to investigations of brain diseases including addiction, autism, Parkinson’s and Alzheimer’s disease, researchers from FAU’s Brain Institute seek to generate knowledge that benefits society. For more information about the Institute and its members, visit http://www.ibrain.fau.edu.

Florida Atlantic University, established in 1961, officially opened its doors in 1964 as the fifth public university in Florida. Today, the University, with an annual economic impact of $6.3 billion, serves more than 30,000 undergraduate and graduate students at sites throughout its six-county service region in southeast Florida. FAU’s world-class teaching and research faculty serves students through 10 colleges: the Dorothy F. Schmidt College of Arts and Letters, the College of Business, the College for Design and Social Inquiry, the College of Education, the College of Engineering and Computer Science, the Graduate College, the Harriet L. Wilkes Honors College, the Charles E. Schmidt College of Medicine, the Christine E. Lynn College of Nursing and the Charles E. Schmidt College of Science. FAU is ranked as a High Research Activity institution by the Carnegie Foundation for the Advancement of Teaching. The University is placing special focus on the rapid development of three signature themes – marine and coastal issues, biotechnology and contemporary societal challenges – which provide opportunities for faculty and students to build upon FAU’s existing strengths in research and scholarship. For more information, visit http://www.fau.edu.