Pieces of the Puzzle
By Jack Mazurak
Research into autism spectrum disorder by a core group of University of Mississippi Medical Center scientists has produced a trail of publications and promising findings stretching back the better part of a decade.
Dr. Rick Lin, professor of neurobiology and anatomical sciences, researches what effects antidepressants have on developing brains, and how those abnormal developments may relate to autism spectrum disorder.
Since 2005, the group’s work with rats has helped connect the use of certain antidepressants affecting the serotonin system with abnormal brain development. Those brain abnormalities coincide with behaviors commonly seen in autism spectrum disorder, or ASD.
The rate of ASD rocketed in U.S. children in the past decades. In 1996, the rate of incidence was less than 1 in 1,000 births, but by 2007 it reached about 1 in 200. The rate of incidence of ASD has roughly doubled every three-to-five years to 1 in 68 currently, according to the Centers for Disease Control and Prevention.
Findings by Dr. Rick Lin, professor of neurobiology and anatomical sciences, and a team with diverse research expertise, suggest that a certain class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) taken during pregnancy might be one factor contributing to a dramatic rise in these developmental disorders in children.
“We saw behaviors in the treated rats and neurological problems that indicate their brains are not properly conducting and processing information,” said Lin, who also holds appointments in the Department of Pediatrics and the Department of Psychiatry and Human Behavior.
“However, based on this work alone, it would be premature to conclude that a pregnant mother should stop taking SSRIs. A pregnant mother may do more harm to her baby through untreated depression than by taking prescribed SSRIs.”
Lin, who grew up in Taiwan before moving to the U.S. in 1969 for master’s and doctoral study, quickly pointed out how the research connects fields, including neuroanatomy, pharmacology, otolaryngology and physiology.
The core UMMC group includes Dr. Ian Paul, professor of psychiatry and human behavior, and Dr. Kimberly Simpson, associate professor of neurobiology and anatomical sciences, along with researchers in pediatrics.
The three began officially working together after Simpson gave a seminar on the brain’s raphe nucleus, the origin point of virtually all serotonin neurons. Since Paul was working on behavior studies with SSRI-treated rats, he asked Lin and Simpson to look for changes in the raphe nuclei of his rats’ brains.
“A couple of weeks later, I got the kind of phone call scientists live for,” Paul said. “Rick called me up and said, ‘Ian, you gotta come see this!’”
Lin and Simpson had found stark differences in how well serotonin neurons developed in the brains of treated versus untreated rats.
“After that, it was a matter of three scientists, their post-docs and students pedaling as hard as we could to figure out what had happened to the brains of those animals and why, and to try to narrow down the precise behaviors affected so that we could connect the changes in the brain with specific changes in behavior,” Paul said.
In 2008, Lin received an Exceptional, Unconventional, Research Knowledge Acceleration, or EUREKA, grant from the National Institutes of Health. The NIH gives those selectively and only to top performers nationally. The $1.3 million grant allowed Lin four years of flexibility to follow the autism research in directions he saw most promising.
“It’s a team effort. If you don’t have a team that works together, you are not going to make those jumps from one field of expertise to another,” said Dr. Rick Lin.
In a 2011 paper, published in the journal Proceedings of the National Academy of Sciences, the researchers described treating rats with the SSRI citalopram during key stages of brain development.
Rats are born at an earlier developmental stage than humans, equivalent to the end of the sixth month of fetal development in humans. Most rats received treatment for two weeks, beginning eight days post-birth, a neurodevelopment period equivalent to the third trimester and early infancy in humans.
In contrast with control-group rats, the investigators found the treated rat pups didn’t want to play and displayed poor social behaviors as adults. The treated rats also showed abnormal responses to changes in their environment, freezing at the sound of a novel tone, or showing little interest in new toys.
Paul, a behavioral research expert, noted that treated male rats more often – and sometimes exclusively – exhibited those abnormal traits. Similarly, ASD is diagnosed more often in human males than females.
Another abnormality common in ASD is a thinner corpus callosum, Simpson said. Like a massive nerve-fiber bridge, the corpus callosum connects the brain’s two halves, sending electrical signals between them.
Lin and Simpson analyzed brain samples of their rats, documenting reduced sizes and connections. They also found unraveled and poorly formed myelin sheathing on neurons in the corpus callosum. Like un-insulated wires arcing, poor myelination can cause signals to be slowed, diverted or lost.
Using the same rats, Dr. Michael Merzenich, professor of otolaryngology and physiology at the University of California San Francisco and member of the National Academy of Science, analyzed their primary auditory cortices, a part of the brain involved in translating sound from the ear into cognitive perception. He found functional abnormalities consistent with ASD.
“The cortex is sluggish and represents sounds with low accuracy. The listening cortex is delayed in development and is impaired into adulthood,” he said.
Delayed development of the ability to understand spoken language is a hallmark of ASD in children, Merzenich said, and contributes to struggles with language and reading.
Subsequent studies include the group’s new paper, accepted this spring by the journal Psychopharmacology. The study helps explain how and which chemical signals in young, developing brains are likely involved in producing lifelong ASD-like behaviors and sensory problems.
Again using rat pups, they tested the citalopram model against various different drugs that, like SSRIs, target the same subcategory of serotonin receptors in the brain. The researchers found no matter which drug the rats received, almost all showed ASD-like behaviors and sensory deficits.
The findings further link increased stimulation of a certain class of receptors in the brain during development to social and sensory abnormalities that last into adulthood.
In a separate study, Lin, Simpson, Paul and other investigators found citalopram exposure decreased the density of serotonin fibers by 40 percent in the brain’s olfactory bulb – a structure involved with communicating smell information. However, they found the change only in male rats, not females.
The results, published in the journal Frontiers in Cellular Neuroscience in May 2013, could point to mechanisms behind sense-of-smell problems often noted in people with ASD.
Now Lin is establishing the Center for Excellence in Developmental Disorders Research, or CEDDR, which would focus on how the brain develops abnormally and what the long-term repercussions are. Investigations may span the human life cycle from prenatal conditions to late-life diseases.
Again pulling from a wide field of experts, Lin wants to draw connections between the roles of parental genetics, mothers’ health, the impact of irregularities in the placenta on early-life inflammation, anatomical abnormalities in the brain, behavioral deficits, and long-term risk for Parkinson’s and other neurodegenerative diseases.
As well, he hopes to start clinical trials for ASD treatment and prevention.
“Rick has a way of surveying the landscape and looking at how he can bring different people together and align their interests, not to just take steps forward but to make leaps,” Simpson explained.
Lin puts it more directly:
“I just want to help the kids.”