Breaking News
January 24, 2019 - Good health literacy linked to better adherence to blood pressure medications among Hispanics
January 24, 2019 - Only a minority of patients in the U.S. with type 1 diabetes achieve treatment goals
January 24, 2019 - High fat reduces efficiency of the immune system to fight infectious disease
January 24, 2019 - Study highlights need for reliable therapeutic targets for prevention, treatment of cardiovascular diseases
January 24, 2019 - Next step toward replacement therapy in type 1 diabetes
January 24, 2019 - “Scientific serendipity” identifies link between type of RNA and autism
January 24, 2019 - Trump Zeroes In On Surprise Medical Bills In White House Chat With Patients, Experts
January 24, 2019 - Unique form of chronic sinusitis found in older patients
January 24, 2019 - NUS researchers make muscle recovery easier for patients with ingenious medical device
January 24, 2019 - Specific cognitive deficits found in individuals with spinal cord injury
January 24, 2019 - An essential reference for diagnostic ultrasonography and biopsy of the thyroid gland
January 24, 2019 - Proteus Digital Health Launches Digital Oncology Medicines to Improve Patient Outcomes
January 24, 2019 - Study looking to prevent type 1 diabetes follows children into adolescence
January 24, 2019 - Nice doctors make a difference
January 23, 2019 - Blood vessel discovery could advance our knowledge of osteoporosis
January 23, 2019 - New esophageal cancer test uses genetic biomarkers to detect changes in esophagal cells
January 23, 2019 - Study evaluates first-ever Robotic Visualization System for neurosurgery
January 23, 2019 - Scientists reveal new mechanism that could lead to specific treatment of strokes and seizures
January 23, 2019 - Both educational level and occupational orientation predict mother’s smoking during pregnancy
January 23, 2019 - How to (gently) get your child to brush their teeth
January 23, 2019 - Short-term hospital readmissions for gun injuries cost $86 million a year | News Center
January 23, 2019 - New certified reference material for testing residual solvents in cannabis
January 23, 2019 - Gene-edited chickens could prevent future flu pandemic
January 23, 2019 - Cardiovascular disease risk begins even before birth
January 23, 2019 - Younger patients receiving kidney transplant more likely to live longer, shows data
January 23, 2019 - Skin samples hold early signs of prion disease, research suggests
January 23, 2019 - Researchers discover how body initiates repair mechanisms that limits damage to myelin sheath
January 23, 2019 - Fecal transplant from certain donors better than others
January 23, 2019 - Risk for Uninsurance in AMI Patients Reduced With Medicaid Expansion
January 23, 2019 - Readmissions reduction program may be associated with increase in patient-level mortality
January 23, 2019 - Fostering translation and communication in medicine and beyond
January 23, 2019 - To Fight Fatty Liver, Avoid Sugary Foods and Drinks
January 23, 2019 - TPU scientists develop new implants that double the rate of bone lengthening in kids
January 23, 2019 - New sessions at Pittcon 2019
January 23, 2019 - Insilico to present latest findings in AI for Drug Discovery at 3rd Annual SABPA FTD Forum
January 23, 2019 - Opioid overdose patients can be safely discharged an hour after administration of naloxone
January 23, 2019 - Scientists find bacterial extracellular vesicles in human blood
January 23, 2019 - Researchers use modified type of flu virus to develop new therapies for prostate cancer
January 23, 2019 - Researchers gain new insights into development of necrotizing enterocolitis in preemies
January 23, 2019 - Medical expert advises people with epilepsy not to stockpile medicines
January 23, 2019 - CDC study explores link between smoking and clinical outcomes of assisted reproductive technology
January 23, 2019 - Study outlines research priorities for improving pediatric patient care and safety
January 23, 2019 - Bedfont to exhibit NObreath FeNO monitor at Arab Health 2019
January 23, 2019 - Nicotinamide riboside supplementation confers significant physiological benefits to mothers and offspring
January 23, 2019 - Increasing temperatures may help preserve crop nutrition
January 23, 2019 - Many Oncologists in the Dark About LGBTQ Health Needs
January 23, 2019 - Epigenetic change causes fruit fly babies to inherit diet-induced heart disease
January 23, 2019 - Erasing memories could reduce relapse rates among drug addicts
January 23, 2019 - African Americans who smoke cigarettes are more likely to develop peripheral artery disease
January 23, 2019 - Unique data combination helps FinnGen researchers to fund links between genetic factors and health
January 23, 2019 - Parents’ mental health problems associated with reactive attachment disorder in children
January 23, 2019 - Graphene Flagship project studies impact of graphene and related materials on our health
January 23, 2019 - The connection between the Pope and contraceptive pills
January 23, 2019 - Prior dengue infection could protect children from symptomatic Zika
January 23, 2019 - Previous dengue virus infection associated with protection from symptomatic Zika
January 23, 2019 - VISTA checkpoint implicated in pancreatic cancer immunotherapy resistance
January 23, 2019 - The Tiny Camera That Could Revolutionize Cardiovascular Surgery
January 23, 2019 - Peptide isolated from soil fungi has antitumor and antibacterial properties
January 23, 2019 - TGen identifies polio-like virus as potential cause of Acute Flaccid Myelitis outbreak
January 23, 2019 - Migrants and refugees do not bring disease and are at greater health risk themselves says WHO
January 23, 2019 - Examing the effects of menopause in workplace
January 23, 2019 - Enemy number 1 – Air pollution and climate change top of WHO agenda
January 23, 2019 - Two Positive Phase III studies of Tafenoquine for the Radical Cure of Plasmodium vivax Malaria Published in The New England Journal of Medicine
January 23, 2019 - World Trade Center responders at increased risk for head and neck cancers
January 23, 2019 - Low-sugar diet leads to significant improvement in nonalcoholic fatty liver disease in boys
January 23, 2019 - Chaos in bodily regulation can optimize our immune system, finds study
January 23, 2019 - Short, text-based exercises can increase happiness for adults recovering from substance use disorders
January 23, 2019 - Body size may have greater influence on women’s lifespan than men
January 23, 2019 - Groundbreaking tool helps visualize neuronal activity with near-infrared light
January 23, 2019 - Prior dengue immunity in children may be protective against symptomatic Zika
January 23, 2019 - Holocaust survivors with PTSD and their offspring exhibit more unhealthy behavior patterns
January 23, 2019 - Scientists discover new genetic mutations causing inherited deaf-blindness
January 23, 2019 - UC team designs new naloxone-dispensing smart device
January 23, 2019 - Torrent Pharmaceuticals Limited Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP and Losartan Potassium and Hydrochlorothiazide Tablets, USP
January 23, 2019 - Brain activity shows development of visual sensitivity in autism
January 23, 2019 - Two hour gap between dinner and sleep is overrated says Japanese research
January 23, 2019 - Fear and embarrassment are causing smear test numbers to plummet
January 23, 2019 - Protein-secreting device implanted in epileptic rats reduces seizures, improves cognition
January 23, 2019 - Reintroduction project recovers current wild population of green turtle in Cayman Islands
January 23, 2019 - Cancer survivors face greater financial burden related to medical bills
Scientists pinpoint pathway that impacts features of autism

Scientists pinpoint pathway that impacts features of autism

image_pdfDownload PDFimage_print
Randy Blakely, Ph.D., senior author, executive director of FAU’s Brain Institute, and a professor of biomedical science in FAU’s Schmidt College of Medicine, and graduate student and co-author Meagan Quinlan. Credit: Florida Atlantic University

A team of scientists at Florida Atlantic University 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).

Currently, there are no FDA-approved medications that improve the core symptoms of ASD. Findings from this study, published in the Proceedings of the National Academy of Sciences (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—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 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 FAU’s Brain Institute, and a professor of biomedical science in FAU’s Schmidt College of Medicine, 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, Zoloft and Lexapro. 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 subtle and effective way to modify brain serotonin signaling.

“We suspected that normally as serotonin signaling changes, neurons turn up or down the activity of this transporter keeping serotonin levels finely balanced,” said Blakely. “We generated evidence for this idea using cultured cells that expressed SERT, but what these observations meant for the brain or brain disorders was unclear.”

In 2005, Blakely and collaborators at Vanderbilt University 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.

“Our years of studying SERT gave us a clue as to how to tone down SERT hyperactivity without eliminating the protein’s normal function,” said Blakely.

A few years before their mutation discovery, Blakely’s team identified an enzyme, p38α 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 p38α 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 “high gear” 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 p38α 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—the first time the trait had been reproduced in animals generated to mimic ASD.

“The 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,” said Blakely.

To test this idea, Blakely needed a drug that could attack brain p38α MAPK potently and specifically. Biochemist D. Martin Watterson, Ph.D., at the Department of Pharmacology at Northwestern University Feinberg School of Medicine and a co-author, came up with the needed tool known as MW150.

“Marty’s drug was really key to our efforts, as it gets into the brain very well, has good selectivity for p38α MAPK, and previously had been demonstrated to be safe to use in animals,” said Matthew J. Robson, Ph.D., first author and an assistant professor in the James L. Winkle College of Pharmacy at the University of Cincinnati. “Remarkably, giving the drug once a day for a week reversed many of the changes induced by the SERT Ala56 mutation.”

Encouraged by these findings, yet knowing that drugs can sometimes act on other targets, Blakely’s team sought another approach to confirm that the drug’s effects were due to blockade of brain p38α MAPK. They decided to eliminate the enzyme only from brain serotonin neurons using a genetic approach called “conditional gene deletion.” The effects with animals lacking a functional p38α MAPK gene mirrored their findings with MW150.

“Although 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,” said Robson. “When 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.”

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 Columbia University 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’s study demonstrated that MW150 also could treat physiological changes linked to gut function in the mice.

“Even 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,” said Blakely. “We 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.”

The SERT Ala56 mutation is relatively rare and found in only about 1 percent of the U.S. population. Even though Blakely’s 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.

“We 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’s role in brain disorders likely goes far beyond depression,” 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.

“It’s been a long road with our research efforts,” said Blakely. “Although 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’t veered from the path. I’m hopeful that our work will prove meaningful beyond the laboratory.”


Explore further:
Novel mouse model for autism yields clues to a 50-year-old mystery

More information:
Matthew J. Robson el al., “p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse,” PNAS (2018). www.pnas.org/cgi/doi/10.1073/pnas.1809137115

Journal reference:
Proceedings of the National Academy of Sciences

Provided by:
Florida Atlantic University

Tagged with:

About author

Related Articles