Deleting a single gene in the cerebellum of mice can cause key autistic-like features , researchers have found. They also discovered that rapamycin, a commonly used immunosuppressant drug, prevented these symptoms.

The deleted gene is associated with Tuberous Sclerosis Complex (TSC), a rare genetic condition. Since nearly 50 percent of all people with TSC develop autism, the researchers believe their findings will help us better understand the condition’s development.

“We are trying to find out if there are specific circuits in the brain that lead to autism-spectrum disorders in people with TSC,” said Mustafa Sahin, Harvard Medical School associate professor of neurology at Boston Children’s Hospital and senior author on the paper. “And knowing that deleting the genes associated with TSC in the cerebellum leads to autistic symptoms is a vital step in figuring out that circuitry.”

This is the first time researchers have identified a molecular component for the cerebellum’s role in autism. “What is so remarkable is that loss of this gene in a particular cell type in the cerebellum was sufficient to cause the autistic-like behaviors,” said Peter Tsai, HMS instructor of neurology and the first author of this particular study.

These findings were published online July 1 in Nature.

TSC is a genetic disease caused by mutations in either one of two genes, TSC1 and TSC2. Patients develop benign tumors in various organs in the body, including the brain, kidneys and heart, and often suffer from seizures, delayed development and behavioral problems.

Researchers have known that there was a link between TSC genes and autism, and have even identified the cerebellum as the key area where autism and related conditions develop.

Previous studies have shown that certain cells essential for cerebellar function called Purkinje cells, which are among the largest neurons in the human brain, are fewer in number in patients with autism. To better understand the relationship between Purkinje cells and autism, Sahin and his team deleted copies of the TSC1 gene in the Purkinje cells of mice. Some mice had only one copy of the gene deleted, while others had both of their copies deleted.

In both cases, deleting this gene caused the three main signs of autistic-like behaviors:Abnormal social interactions. The mice spent less time with each other and more with inanimate objects, compared to controls.Repetitive behaviors. The mice spent extended amounts of time pursuing one activity or with one particular object far more than normal.Abnormal communication. Ultrasonic vocalizations, the communication method used among rodents, were highly distressed.

The researchers also tested learning. “These mice were able to learn new things normally,” said Tsai, “but they had trouble with ‘reversal learning,’ or re-learning what they had learned when their environment changed.”

Tsai and colleagues tested this by training the mice to swim a particular path in which a platform where they could rest was set up on one side of the pool. When the researchers moved the platform to the other side of the pool, the mice had greater difficulty than the control mice re-learning to swim to the other side.

“These changes in behavior indicate that the TSC1 gene in Purkinje cells, and by extension, the cerebellum, are a part of the circuitry for autism disorders,” emphasized Sahin.

The researchers also found that the drug rapamycin averted the effects of the deleted gene. Administering the drug to the mice during development prevented the formation of autistic-like behaviors.

Currently, Sahin is the sponsor-principal investigator for an ongoing Phase II clinical trial to test the efficacy of everolimus, a compound in the same family as rapamycin, in improving neurocognition in children with TSC. The trial will be open for enrollment until December 2013.

“Our next step will be to see how the abnormalities in Purkinje cells affect autism-like development. We don’t know how generalizable our current findings are, but understanding mechanisms beyond TSC genes might be useful to autism,” said Tsai.

The amygdala (in red) grows too rapidly in babies (6-12 months) who later develop autism as toddlers.CREDIT (CIDD at UNC-CH)

The amygdala is a small structure deep in the brain important for interpreting the social and emotional meaning of sensory input – from recognizing emotion in faces to interpreting fearful images that inform us about potential dangers in our surroundings. Historically the amygdala has been thought to play a prominent role in the difficulties with social behavior that are central to autism.

Researchers have long known the amygdala is abnormally large in school-age children with autism, but it was unknown precisely when that enlargement occurs. Now, for the first time, researchers from the Infant Brain Imaging Study (IBIS) Network, used magnetic resonance imaging (MRI) to demonstrate that the amygdala grows too rapidly in infancy. Overgrowth begins between six and 12 months of age, prior to the age when the hallmark behaviors of autism fully emerge, enabling the earliest diagnosis of this condition. Increased growth of the amygdala in infants who were later diagnosed with autism differed markedly from brain-growth patterns in babies with another neurodevelopmental disorder, fragile X syndrome, where no differences in amygdala growth were observed. 

Published in the American Journal of Psychiatry, the official journal of the American Psychiatric Association, this research demonstrated that infants with fragile X syndrome already exhibit cognitive delays at six months of age, whereas infants who will later be diagnosed with autism do not show any deficits in cognitive ability at six months of age, but have a gradual decline in cognitive ability between six and 24 months of age, the age when they were diagnosed with Autism Spectrum Disorder in this study. Babies who go on to develop autism show no difference in the size of their amygdala at six months. However, their amygdala begins growing faster than other babies (including those with fragile X syndrome and those who do not develop autism), between six and 12 months of age, and is significantly enlarged by 12 months. This amygdala enlargement continues through 24 months, an age when behaviors are often sufficiently evident to warrant a diagnosis of autism. 

“We also found that the rate of amygdala overgrowth in the first year is linked to the child’s social deficits at age two,” said first author Mark Shen, PhD, Assistant Professor of Psychiatry and Neuroscience at UNC Chapel Hill and faculty of the Carolina Institute for Developmental Disabilities (CIDD). “The faster the amygdala grew in infancy, the more social difficulties the child showed when diagnosed with autism a year later.”

This research – the first to document amygdala overgrowth before symptoms of autism appear – was conducted through The Infant Brain Imaging Study (IBIS) Network, a consortium of 10 universities in the United States and Canada funded through a National

Institutes of Health Autism Center of Excellence Network grant.

The researchers enrolled a total of 408 infants, including 58 infants at increased likelihood of developing autism (due to having an older sibling with autism) who were later diagnosed with autism, 212 infants at increased likelihood of autism but who did not develop autism, 109 typically developing controls, and 29 infants with fragile X syndrome. More than 1,000 MRI scans were obtained during natural sleep at six, 12, and 24 months of age.

So, what might be happening in the brains of these children to trigger this overgrowth and then the later development of autism? Scientists are starting to fit the pieces of that puzzle together.

Earlier studies by the IBIS team and others have revealed that while the social deficits that are a hallmark of autism are not present at six months of age, infants who go on to develop autism have problems as babies with how they attend to visual stimuli in their surroundings. The authors hypothesize that these early problems with processing visual and sensory information may place increased stress on the amygdala, leading to overgrowth of the amygdala.

Amygdala overgrowth has been linked to chronic stress in studies of other psychiatric conditions (e.g., depression and anxiety) and may provide a clue to understanding this observation in infants who later develop autism. 

Senior author Joseph Piven, MD, Professor of Psychiatry and Pediatrics at the University of North Carolina at Chapel Hill added, “Our research suggests an optimal time to start interventions and support children who are at highest likelihood of developing autism may be during the first year of life. The focus of a pre-symptomatic intervention might be to improve visual and other sensory processing in babies before social symptoms even appear.”

Leading autism researchers, clinicians, and advocates from around the world to gather to share latest findings and discoveries

2022 Lifetime Achievement Award will honor Sally Rogers

2022 INSAR Advocate Award will honor Simons Foundation Co-Founders
Jim and Marilyn Simons

The International Society for Autism Research (INSAR) will hold its 2022 Annual Meeting – the organization’s 21^st – from Wednesday, May 11 through Saturday, May 14, 2022, bringing together a global, multidisciplinary group of hundreds of autism researchers, clinicians, advocates, self-advocates, and students to exchange the latest scientific learnings and discoveries that are advancing the growing understanding of autism. This year’s meeting will be held in a hybrid format, with in-person presentations and events that will be available virtually to registered attendees. Participants are invited to attend the conference in-person at the JW Marriott Austin Hotel in Austin, TX, USA or participate virtually through the online platform and mobile app, which will be available to all registrants.

The INSAR Annual Meeting is the world’s largest gathering of researchers and other stakeholders who continue to catalyze innovative research into all aspects of autism spectrum disorder, including its nature, causes, and treatments. The 21^st INSAR Annual Meeting will include in-person and virtual presentations of oral papers and posters, panel sessions, and demonstrations of new and emerging technologies. Former INSAR President Dr. Sally Rogers, a leading, highly respected researcher of the development and treatment of autism in young children, and co-developer of the pioneering Early Start Denver Model (ESDM), will be honored with the INSAR Lifetime Achievement Award. This year’s INSAR Advocate Award will honor Jim and Marilyn Simons, co-founders of the Simons Foundation,
for their pioneering and enduring support of groundbreaking autism science. The 2022 INSAR Annual Meeting will also recognize the soon-to-be-announced recipients of the INSAR Cultural Diversity Research Award, Slifka / Ritvo Innovation in Autism Research Award, INSAR Early Career Investigator Awards, and Dissertation Awards. Awards will also be presented to autistic researchers, and students involved in autism research. More than 1,300 abstracts with authors from over 20 countries have been accepted for presentation. 

An in-person press conference will be held on Wednesday, May 11 at 12PM EDT / 11AM CDT that will focus on highlighted notable research. It will also be live-streamed on the INSAR Facebook page.

To register to attend the INSAR Annual Meeting in-person or virtually, visit the INSAR website. INSAR Membership is not required.

Media wishing to attend must register in advance here.

Research will be presented on topics including:

• Brain Structure (MRI, neuropathology)  
• Communication and Language  
• Early Development (< 48 months)           
• Epidemiology
• Genetics
• Social Cognition and Social Behavior
• Family Issues & Stakeholder Experiences (Telemedicine effectiveness)

Keynote speakers:

Damien Fair

Sally Rogers (Lifetime Achievement Award)

Liz Pellicano

Joseph Buxbaum

Evdokia Anagnostou

Autism Awareness Month each April – but does it actually lead to increased autism awareness? According to a new analysis of web search trends by researchers at Drexel University, it does appear to drive an increase in Google searches for autism – by a third over searches in March in recent years.

Brian K. Lee, PhD, an assistant professor in the Drexel University School of Public Health and research fellow of the A.J. Drexel Autism Institute, was senior author of the study with public health doctoral student Elizabeth DeVilbiss, published early online this month in the Journal of Autism and Developmental Disorders.

Using the Google trends tool (google.com/trends), they analyzed web search queries for the terms “autism” and “Asperger’s” from January 2004 through April 2014 in the United States. They also compared these trends with searches for “ADHD” to assess the possible influence of broader trends in public interest in mental health issues of special interest to younger populations.

Each April, from 2004 through 2014 (except 2005), web search interest in autism spiked – up by an average of 26 percent between March and April, followed by an average decrease by 24 percent between April and May. Even sharper April spikes have occurred from 2007 through 2014, with the average March-April increase at 33 percent in those years.

A secondary, smaller increase in “autism” searches occurred each fall. Similar spring and fall oscillations occurred in searches for “ADHD” but without the sharp spike observed in April for “autism.” The spring and fall oscillations may reflect a rebound in web searches in general, which tend to drop off in summer and winter, Lee said.

The overall search interest in “autism” was sustained but not increasing over the ten-year span the researchers analyzed. In contrast, “Asperger’s” searches had a long-term increasing trend, with the term’s popularity overall 255 percent higher in January 2014 in comparison to January 2004.

Lee and DeVelbiss pointed out a few additional spikes in the search trends that may correspond to high-impact media coverage of autism and Asperger’s disorder outside of the April awareness campaigns. The Google trends tool allows users to overlay related news headlines for search terms alongside the trend chart. Lee warned that conclusions about the correlation of news headlines to search trends should be considered with caution because many could be simply accidental correlations. However, three non-April spikes were of particular note:

• In September 2007, the largest monthly increase (80 percent) in searches for “autism” during the 2004-2014 span occurred. In this month, The Oprah Winfrey Show aired a high-profile segment on September 18 featuring Jenny McCarthy and Holly Robinson Peete discussing their sons with autism.
• In February 2005, another peak in “autism” searches occurred, correlating with a 10-part series on autism on The Today Show, February 21-25, 2005.
• In December 2012, searches for “Asperger’s” increased by 122 percent over November 2012. This increase corresponded with heavy publicity regarding the planned elimination of Asperger’s as a standalone diagnosis in the DSM-V.

Autism is not the only condition for which awareness months have been linked to increased search activity. A 2011 study in BMC Cancer reported that searches for breast cancer increased each October during Breast Cancer Awareness Month between 2004 and 2009, but much lower search activity occurred for prostate and lung cancers during their respective awareness months. Search activity is also far from the entire picture of creating awareness of autism and other conditions. Whether useful and accessible information is available as a result of that search is important.

“Whether increased awareness is meaningful is another question,” Lee said. “When a parent performs a web search, does it lead to recognition of autism in their child? Does it lead to seeking clinical testing and services?” Search trends can’t answer those questions, but can provide a glimpse of public interest in a topic.