In a new study published today in Cell Reports, researchers from the Donald K. Johnson Eye Institute (DKJEI), part of the Krembil Research Institute at University Health Network, have identified previously unknown connections between genetic factors in Autism ).

This neurodevelopmental disorder is associated with a wide range of physiological and behavioural symptoms, including deficits in communication, cognition and motor function, as well as seizures and hyperactivity.  

Autism, which affects one in 50 Canadians between the ages of 1-17, has been linked to hundreds of risk genes that could play a role in disease development.

“We still do not know how different genetic risk factors lead to autism, whether they act independently or through similar molecular pathways to cause the condition. We also don’t know when, or even where, in the brain these genes are expressed and cause the cellular defects that leads to autism. Do defects occur during fetal development, after a child is born, or at some later point in their lifespan?” says Dr. Karun Singh, a Senior Scientist at the DKJEI.

“Our goal for this study was to clarify the roles of specific risk genes in autusm , and whether different genes converge onto common pathways that regulate cell functions, such as energy production and metabolism.”

Most autism risk genes produce proteins that are involved in important cellular functions. In this study, the research team used a protein mapping tool to study 41 risk genes associated with autism, many of which were not previously known to interact with each other.

One of the team’s major findings was that several of the risk genes modulate the activity of mitochondria, the energy factories within cells. Since brain cells are metabolically very active, disruptions to their mitochondrial function can impact brain function.

“The link between autism risk genes and mitochondrial dysfunction sheds light on how mutations in these genes might change brain cell activity and ultimately cause disease symptoms,” says Dr. Nadeem Murtaza, a postdoctoral researcher in Dr. Singh’s lab.

The study also revealed that the protein-based mapping tool could be used to help classify individuals with autiusm who have a shared biological signature. Since autism is a highly variable disorder, grouping individuals based on the biological factors underlying their symptoms could help researchers develop more tailored treatments in future.

“There is a lot of opportunity for change to occur between the level of the gene sequences, which we are getting a pretty good handle on, and what actually manifests in the patient,” adds Dr. Murtaza.

“People who have different forms of a genetic disorder might be more connected than we think at the biological level,” says Dr. Murtaza.

The protein-mapping technology used in this study has the potential to improve our understanding of brain function, and can be applied to numerous other brain diseases.

The next step is to apply this technology to patient-specific brain tissue generated in Dr. Singh’s lab, where stem cells from a patient’s blood are developed into three-dimensional brain tissues that exhibit that patient’s unique gene and protein profiles.

“It would enable us to study a patient’s particular disease mechanisms and eventually, test the effectiveness of different therapies,” says Dr. Singh.

“This innovative approach will open the door to these technologies being used more widely and being applied to other diseases as well,” he adds. “Working with colleagues here at Krembil, with programs that span a vast array of neurodegenerative, arthritis and vision-related disorders, is a great way to leverage this technology and our present findings.”

Scientists looking to understand the fundamental brain mechanisms of autism spectrum disorder have found that a gene mutation known to be associated with the disorder causes an overstimulation of brain cells far greater than that seen in neuronal cells without the mutation.

The Rutgers-led study, spanning seven years, employed some of the most advanced approaches available in the scientific toolbox, including growing human brain cells from stem cells and transplanting them into mouse brains.

The work illustrates the potential of a new approach to studying brain disorders, scientists said.

Describing the study in the journal, Molecular Psychiatry, researchers reported a mutation – R451C in the gene Neurologin-3, known to cause autism in humans – was found to provoke a higher level of communication among a network of transplanted human brain cells in mouse brains. This overexcitation, quantified in experiments by the scientists, manifests itself as a burst of electrical activity more than double the level seen in brain cells without the mutation.

“We were surprised to find an enhancement, not a deficit,” said Zhiping Pang, an associate professor in the Department of Neuroscience and Cell Biology in the Child Health Institute of New Jersey at Rutgers Robert Wood Johnson Medical School and the senior author on the study. “This gain-of-function in those specific cells, revealed by our study, causes an imbalance among the brain’s neuronal network, disrupting the normal information flow.”

The interconnected mesh of cells that constitutes the human brain contains specialized “excitatory” cells that stimulate electrical activity, balanced by “inhibitory” brain cells that curtail electrical pulses, Pang said. The scientists found the oversized burst of electrical activity caused by the mutation threw the mouse brains out of kilter.

Autism is a developmental disability caused by differences in the brain. About 1 in 44 children have been identified with the condition , according to estimates from the Centers for Disease Control and Prevention.

Studies suggest autism could be a result of disruptions in normal brain growth very early in development, according to the National Institutes of Health’s National Institute of Neurological Disorders and Stroke. These disruptions may be the result of mutations in genes that control brain development and regulate how brain cells communicate with each other, according to the NIH.

“So much of the underlying mechanisms in autism are unknown, which hinders the development of effective therapeutics,” Pang said. “Using human neurons generated from human stem cells as a model system, we wanted to understand how and why a specific mutation causes autism in humans.”

Researchers employed CRISPR technology to alter the human stem cells’ genetic material to create a line of cells containing the mutation they wanted to study, and then derived human neuron cells carrying this mutation. CRISPR, an acronym for clustered regularly interspaced short palindromic repeats, is a unique gene-editing technology.

In the study, the human neuron cells that were generated, half with the mutation, half without, were then implanted in the brains of mice. From there, researchers measured and compared the electrical activity of specific neurons employing electrophysiology, a branch of physiology that studies the electrical properties of biological cells. Voltage changes or electrical current can be quantified on a variety of scales, depending on the dimensions of the object of study.

“Our findings suggest that the NLGN3 R451C mutation dramatically impacts excitatory synaptic transmission in human neurons, thereby triggering changes in overall network properties that may be related to mental disorders,” Pang said. “We view this as very important information for the field.”

Pang said he expects many of the techniques developed to conduct this experiment to be used in future scientific investigations into the basis of other brain disorders, such as schizophrenia.

“This study highlights the potential of using human neurons as a model system to study mental disorders and develop novel therapeutics,” he said.

A research team led by ORNL’s Michael Garvin, left, and David Kainer discovered genetic mutations called structural variants and linked them to autism spectrum disorders, demonstrating an approach that could be used to develop better diagnostics and drug therapies.

An Oak Ridge National Laboratory-led research team discovered genetic mutations that underlie autism using a new approach that could lead to better diagnostics and drug therapies.

Scientists estimate 80% of autism is inherited, but they have yet to identify causative genes.

“We realized the value of unexplored heritable information from others’ research,” said ORNL’s Michael Garvin. Garvin and colleagues focused on genomic mutations called structural variants and established a direct link to autism traits.

The key was observing that many structural variants are excluded because they often display nontraditional inheritance patterns. By focusing on these variants, ORNL scientists found a mutation in the ACMSD gene that is associated with nonverbal types of autism. They then used artificial intelligence and high-performance computing to find additional variants related to three autism subtypes.

“We’ve established a workflow for using this often-ignored data that can be applied not only to autism, but also to other disorders,” said ORNL’s David Kainer. 

New study results from an international research team led by USC scientists have identified a signature pattern of white matter connectivity exclusive to the brains of autistic people distinct from that in the brains of people with developmental coordination disorder (DCD).

Their findings appear today in Scientific Reports. 

Approximately 85 percent of autistic people have been, or likely could be, diagnosed with DCD, a condition that interferes with learning and motor control. DCD can impair everyday activities such as typing, dressing or walking, which can subsequently diminish one’s social participation and satisfaction. 

Distinguishing between the brain activity patterns of autism and DCD populations is critical because the widespread comorbidity of autism and DCD confounds previous autism research which, at the time it was conducted, was understood to be exclusively investigating its core social–communication symptoms.

“As the scientific community has learned more and more about DCD, we’ve realized that white matter differences previously identified in the autism literature could actually be attributed to this underlying motor comorbidity,” said Lisa Aziz-Zadeh, the study’s senior author. “In fact, that’s exactly what our team found — that many prior research findings are probably not actually reflecting autism’s core symptoms, but are more likely a reflection of co-occurring DCD.” 

Aziz-Zadeh is an associate professor at the USC Chan Division of Occupational Science and Occupational Therapy, with joint appointments at the USC Dornsife College of Letters, Arts and Sciences’ Brain and Creativity Institute and the Department of Psychology. She is the director of the USC Center for the Neuroscience of Embodied Cognition, which is managing research projects funded by the National Institutes of Health, U.S. Department of Defense and the Office of the Director of National Intelligence’s Intelligence Advanced Research Projects Activity. 

Aziz-Zadeh and colleagues used diffusion weighted MRI, a technique for observing functional brain connectivity, in children and teens from 8 to 17 years old assigned to one of three study groups: those with autism; those with probable DCD; and typically-developing individuals. The images were analyzed, compared and correlated to motor and social behavior assessments which the participants had also completed.

The researchers found that many structural brain connectivity patterns previously believed to be related to autism also overlap with DCD. The team was able to pinpoint three white matter pathways demonstrating distinctly different connectivity, unique to the research participants with autism, as compared to the DCD and typically developing groups: the longitudinal fibers and u-fibers of the mid-cingulum, the corpus callosum forceps minor/anterior commissure and the left middle cerebellar peduncle. These differences also correlated with autistic participants’ measures of emotional performance and/or autism severity. The brains of children with DCD demonstrated unique white matter patterns in the left cortico-spinal and cortico-pontine tracts. 

“These results show that we can use advanced imaging to distinguish between autism’s hallmark social symptoms and other motor-related symptoms at the level of brain anatomy,” said Emily Kilroy, the publication’s first author and former post-doctoral scholar in Aziz-Zadeh’s lab during the study’s data collection period. “Of course, people are so much more than their brain anatomy, but this degree of clarity and specificity at the anatomical level gets us one step closer to understanding the biological basis and expression of autism.” 

 Part of understanding the underlying causes of autism relies on figuring out which cells’ signaling patterns in the brain are disrupted, and when during nervous system development the disruption occurs.

New research findings in mouse models of one genetic risk for autism support the idea that loss of a specific gene interferes with cells in the brain whose role is to inhibit signaling. Though there are fewer of these cells than other neurons and their signals don’t travel very far, they have enormous influence on patterns of information transmission within the brain and to the rest of the body.

Ohio State University researchers found that deleting a copy of the autism-risk gene Arid1b from specific brain cells decreased the number of inhibitory cells and lowered signaling between inhibitory cells and the excitatory cells they help control. Previous research has suggested reduced inhibitory signals in mouse models of the disorder result in a range of autism-related behaviors.

In separate experiments, the scientists found that signaling changes linked to inhibitory cells can be seen in the same genetic mouse models of autism spectrum disorder (ASD) very shortly after birth, but the disruption might not be strong enough to interfere with normal brain development powered by a host of other genes.

Studying disease risk genes’ effects on brain circuitry is intended to pave the way to possible therapies, but this pursuit also offers insights into how normal circuits function because “in many cases, that’s still a mystery,” said senior author Jason Wester, assistant professor of neuroscience in Ohio State’s College of Medicine.

“The circuits are the level of analysis that are crucial for understanding brain function – that’s a key to understanding not just what goes awry in neurodevelopmental disorders, but also to understanding how normal circuits work,” Wester said. “We’re asking what neurodevelopmental disorders can tell us about how normal circuits work – and what that tells us about how we go about trying to fix disrupted circuits.”

The research posters were presented today (Monday, Nov. 14, 2022) at Neuroscience 2022, the annual meeting of the Society for Neuroscience.

There are many genes associated with risk for ASD, which is among the reasons it is such a difficult disorder to study and treat. In fact, in a recent data-mining RNA sequencing study, Wester’s lab created the first organized list of genes that relate to formation of synapses – vehicles for circuit transmission among cells – across the brain.

“We hoped to provide clues for whether or not we might consider therapies for autism that could be fixable across the whole brain if we tweaked a single gene,” he said. “Unfortunately, we found it’s not likely. Autism risk genes are not concentrated in a specific group. But we did find many among inhibitory neurons, suggesting they are potentially key targets for therapeutics.”

Wester deletes one copy of the Arid1b gene in specific brain cells in mice – rather than throughout the body in the way natural gene loss would occur – to examine where circuit changes go wrong in ways that could lead to symptoms associated with autism, such as problems with social communication, repetitive behaviors, learning deficits or anxiety.

“We knock out the gene in a subpopulation of cells to investigate their contributions to circuit abnormalities, and look at changes in synaptic properties during development over time and compare them to control mice,” he said.

In examinations of circuit development in brain slices, the researchers found that loss of the gene from excitatory neurons has only subtle effects on signaling, which suggests, in this mouse model, that loss of the gene in excitatory cells is not a likely driver of autism-related behavioral abnormalities.

Loss of the gene in inhibitory neurons, however, led to changes in synaptic physiological functions and connectivity at varying levels depending on their location in the cortex.

The team also monitored hippocampus activity in the brains of 1-week-old mice lacking a copy of the Arid1b gene in brain cells to see if genetic problems affected circuitry at that very early stage. They found some delays in synapse development and lower frequency of information transmission involving inhibitory neurons, but normal hippocampal development appeared to occur despite those changes. Though it’s too soon to tell, this finding could have implications for potential timing of interventions related to repairing damaged circuity, Wester said.

Precision in understanding brain circuitry is vital to the design of therapies to address ASD.

“Our data indicate that in some cases, circuits between excitatory and inhibitory cells seem normal, but circuits right next to them consisting of slightly different subtypes of neurons are the ones that are disrupted – so if you dial up inhibition everywhere and dial it up in the wrong places, you could introduce a whole new host of problems,” he said.

“That’s why what we’re doing is valuable, because it can tell us where to target interventions and open up new avenues for therapies.”