News - Schumann Lab

By Nadine A Yehya

Read the original post in UC Davis Health News

Genes involved in inflammation, immune response and neural connectivity behave differently in brains of people with autism

(SACRAMENTO)

A new study led by UC Davis MIND Institute researchers confirms that brain development in people with autism differs from those with typical neurodevelopment. According to the study published in PNAS, these differences are linked to genes involved in inflammation, immunity response and neural transmissions. They begin in childhood and evolve across the lifespan.

About one in 44 children in the U.S. has autism. Autistic individuals may behave, communicate and learn in ways that are different from neurotypical people. As they age, they often have challenges with social communication and interaction.

The researchers aimed to understand how neurons in the brain communicate and the interaction between age and autism. They studied the genetic differences in brain neurons in people with autism at different ages and compared them to those with neurotypical development.

Earlier studies have shown that certain brain regions mark early excess, followed by reductions in volume, connectivity, and cell densities of neurons as people with autism age through adulthood.

“Initial excess and overconnectivity of neurons may make the brain more vulnerable to early aging and inflammation, which may lead to further changes in the brain structure and function,” said co-senior author Cynthia Schumann. Schumann is a professor of neuroscience in the Department of Psychiatry and Behavioral Sciences. She is affiliated with the UC Davis MIND Institute. “Understanding how the brain in a person with autism changes throughout life will provide opportunities for early intervention.”

Cynthia Schumann wearing a white coat and looking through a microscope. — Cynthia Schumann, professor of neuroscience, is affiliated with UC Davis MIND Institute

Method

The researchers analyzed brain tissues from 27 deceased individuals with autism and 32 without autism. The age of these individuals ranged between 2 and 73 years.

The tissues were taken from the superior temporal gyrus (STG) region — an area in the brain responsible for sound and language processing and social perception.

“The STG plays a critical role in integrating information. It helps provide meaning about our surroundings. Despite its importance, it remains relatively unexplored,” Schumann commented. “We wanted to understand how the molecular changes in this critical part of the brain are happening in autism.”

The team analyzed brain tissues as well as isolated neurons using laser capture microdissection techniques. They studied mRNA expression on a molecular level in the STG tissue and the isolated neurons. The mRNA translates the DNA code into instructions the cell machinery can recognize and use to make proteins for different body functions.

Main findings

The study identified 194 significantly different genes in the brains of people with autism. Of those genes, 143 produced more mRNA (upregulated) and 51 produced less (downregulated) in autistic brains than in typical ones.

The downregulated genes were mainly linked to brain connectivity. This may indicate that the neurons may not communicate as efficiently. Too much activity in the neurons may cause the brain to age faster in autistic individuals.

The study also found more mRNA for heat-shock proteins in autistic brains. These proteins respond to stress and activate immune response and inflammation.

“The findings from our study are really important in understanding what is happening in the brains of people with autism. Identifying these changes over time gives us an opportunity to think about some interventions that might be more useful in certain periods.”
— Cynthia Schumann, professor of neuroscience affiliated with UC Davis MIND Institute

Age-related brain differences between neurotypical and autistic people

The study identified 14 genes in bulk STG tissue that showed age-dependent differences between autistic and neurotypical individuals and three genes in isolated neurons. These genes were connected to synaptic as well as immunity and inflammation pathways.

Boryana Stamova smiling to the camera — Boryana Stamova is an associate professor at the Department of Neurology.

For example, in typical brains, the expression of the HTRA2 gene is much higher before age 30 and decreases with age. In the STG neurons of people with autism, the expression levels of this gene begin lower and increase with age.

“Changes in HTRA2 have been implicated in neuronal cell loss and cell functions – such as proper protein folding, and reusing and recycling cell components,” explained co-senior author Boryana Stamova, associate professor in the Department of Neurology. She is also affiliated with the MIND Institute. “HTRA2’s role is vital for normal brain function.”

The researchers also uncovered different inflammation patterns in autistic brain tissues. Several immune and inflammation-related genes were strongly upregulated, indicating immune dysfunction that may get worse with age.

The study pointed to an age-related decrease in the gene expression involved in Gamma-aminobutyric acid (GABA) synthesis. GABA is a chemical messenger that helps slow down the brain. It works as an inhibitory neurotransmitter.

Image of inhibitory (GABA) cells in fuchsia and excitatory (vGLUT) cells in red and yellow on a black background — Excitatory neurons (vGLUT; tells neurons to fire) in red and yellow and inhibitory neurons (GABA; tells neurons to stop firing) in fuchsia.

“GABA is known for producing a dampening effect in controlling neuronal hyperactivity in anxiety and stress. Our study showed age-dependent alterations in genes involved in GABA signaling in brains of people with autism,” Stamova said.

The study found direct molecular-level evidence that insulin signaling was altered in the neurons of people with autism. It also noted significant similarities of mRNA expressions in the STG region between people with autism and those with Alzheimer’s disease. These expressions may be linked to increased likelihood of neurodegenerative and cognitive decline.

“The findings from our study are really important in understanding what is happening in the brains of people with autism. Identifying these changes over time gives us an opportunity to think about some interventions that might be more useful in certain periods,” Schumann said.

Cynthia Schumann is wearing a white coat and examining a brain tissue sample on a slide. She is showing the slide to the post-doctoral student next to her. — Professor Cynthia Schumann in her laboratory with the post-doctoral student Kari Hanson

Credits

The study’s co-authors are Bradley Ander of the UC Davis MIND Institute and the Department of Neurology; Alicja Omanska of the UC Davis MIND Institute and the Department of Psychiatry and Behavioral Sciences; and Michael Gandal and Pan Zhang of UCLA.

The researchers are grateful to the families of the brain donors for their invaluable gift to autism research. Brain tissues were provided by the University of Maryland Brain and Tissue Bank, Autism Tissue Program (now Autism BrainNet), Brain Endowment for Autism Research Sciences (BEARS) at the UC Davis MIND Institute, and the Harvard Brain Tissue Resource Center.

This work is supported by National Institutes of Health (NIH) grants MH108909 and the Intellectual and Developmental Disabilities Research Center at UC Davis (1U54HD079125). The study also benefited from NIH instrumentation funding (S10RR-023555, S10OD-018174) for the laser capture microdissection and RNA sequencing.

Autism BrainNet relies on the teamwork of many clinical and research staff to acquire and distribute the tissue provided by our donor families. This staff is located at three centers, or nodes, across the United States. We recently spoke with Alicja Omanska, tissue coordinator of Autism BrainNet Sacramento node, to learn more about her role and experience working for Autism BrainNet.

By Lilliam Acosta-Sanchez and Serena Bianchi

The interview has been edited for clarity and brevity.

Alicja Omanska, M.S.

How did you become interested in autism research and involved with Autism BrainNet?
When I started, which was over 20 years ago, autism spectrum disorder wasn’t a mainstream subject. There isn’t anyone on the spectrum in my family, so autism wasn’t a topic that I was very familiar with. In college, I majored in genetics, and after graduating, I went to work directly in the lab of David Amaral, who is now Autism BrainNet’s scientific director. It was a shock to learn how many individuals are affected by autism, and the fact that there really isn’t a definite cause or a reliable treatment.

As a geneticist, I like solving puzzles, and this became a puzzle to me. Moving forward many years, I was working with Cynthia Schumann, director of Autism BrainNet Sacramento node, as her lab manager. Schumann saw the need for brain tissue for autism research and established a brain bank called BEARS, which is the Brain Endowment for Autism Research Sciences. Our research was extremely limited due to the fact that there weren’t many cases available to study. When Autism BrainNet was created, I felt that it would be a wonderful way to help the research community investigate the causes of autism and explore potential avenues for treatments.

Autism BrainNet has come a long way. We have over 200 brains in our program, but we certainly need more. As you mention it, donations are important to help the research community learn more about autism.
It is challenging to procure a brain of an individual with autism because of the age group. As donors are often young, it is tough to approach a family who may not be thinking about brain donation at such a difficult time. Compared to other conditions, such as Alzheimer’s disease, which is in most cases a disorder of the elderly, it is very difficult to obtain donations from a younger age group, especially in cases of sudden and unexpected death.

What is your role for Autism BrainNet?
I’m the tissue coordinator for the Autism BrainNet Sacramento node. My responsibility is to manage the donation process, from the time we get a notification about a potential donor to receiving and processing the donation in our lab. I also make sure that tissue is properly maintained, stored, logged into the database, and appropriately distributed for research studies requests. As our protocols are continuously adapting to meet our research needs. I also troubleshoot new procedures and design custom equipment.

You worked with Schumann as her lab manager and you’ve been in this line of work for a long time. You’re also a geneticist. What do you see as one of the biggest findings in the field of autism research?
What amazes me is how incredibly diverse the classification of this condition has become over the last 20 years. As a scientist and a mother, I wonder about additional risk factors that are continuously attributed: Is it a genetic predisposition, is there an environmental component, or is it a combination of both? Even though progress has been made toward understanding the causes of autism, there is still much to learn about this condition and its different manifestations.

Why is it important to conduct studies of the postmortem human brain to advance autism research?
Autism is a condition that affects the brain, so we must have something to study it on. Without postmortem brain tissue, we wouldn’t be able to do the type of studies that might lead towards figuring out the underlying causes and mechanisms. There are studies of the brain in living individuals (e.g., studies using magnetic resonance imaging [MRI] techniques) that can examine, for example, how different parts of the brain change as we grow up, but these studies would not allow researchers to look into the structure of neurons and see how neurons are connected and how they function. For that we need to have brain samples.

What has been the most rewarding aspect of your collaboration with Autism BrainNet?
I think the most rewarding part is knowing that I can make a difference in somebody’s life. When you have a child, you want what’s best for them, and when they are sick, you feel absolutely helpless. I hope that the type of research that Autism BrainNet promotes will aid in establishing treatments and improving lives of individuals.

How do you see the role of postmortem brain tissue in moving autism research forward?
We need to know why and how this condition is happening. There are many factors that act together, and this makes it a lot more difficult to study. This is why it is important that we’ll keep on acquiring donations and that researchers become interested in brain tissue studies. Autism is a complex condition and different researchers may just be able to chip away at it by having this resource available.

Meet our team: A conversation with Alicja Omanska, tissue coordinator of Autism BrainNet Sacramento node

Schumann Lab

UC Davis study uncovers age-related brain differences in autistic individuals