Brain imaging studies of infants with autism have shown a faster rate of expansion of a layer of the brain called the cortex in those who go on to be diagnosed with autism. Some infants also exhibit macrocephaly (larger than expected overall brain size). However, little is known about these features in autism. This study will develop a new model system utilizing organoids, which are aggregates of cells obtained directly from individual study participants and then further manipulated in a dish to recreate the cortex. In this way, scientists can understand how cells divide, expand, and grow. This researcher will then compare features in the organoids with brain scans collected from the same individual. This work will provide the research community with a novel way to test therapies and interventions on those with macrocephaly.
Can Brain Size Predict Autism? Building a model system with iPSC-derived cortical organoids
Most of the genetic research conducted to understand rare genetic forms of autism has been focused on the coding regions of the DNA. In genetics, the coding regions are specific parts of the DNA sequence that directly encode instructions for building proteins. There is still a lack of knowledge around the non-coding regions of the genome, which do not contain instructions to make proteins but rather regulate how genes are turned on and off. Recent studies have shown that the non-coding regions play an integral role in brain development. This study will look at over 700,000 non-coding variants in autism to determine their role and importance.
Following the initial analysis, regions that are determined to play a role in the coding of a gene called SCN2A will be targeted. SCN2A is a protein that controls how cells turn on and off, and is strongly tied to both autism and epilepsy. Identifying and validating the enhancers of ASD-associated genes like SCN2A will help scientists better understand mechanisms behind genetic influence of autism and comorbid features, and will also provide novel therapeutic targets for single gene disorders.
This project is graciously co-funded by FamilieSCN2A, the patient advocacy group that supports families with this genetic variation.
Compared to people without autism, the risk of Alzheimer’s disease is 2.6 times higher in people with autism, and they are twice as likely to die prematurely – with autistic women being at even higher risk for premature death. However, very few research studies focus on or even include autistic adults who are middle aged and older. This project capitalizes on a cohort of older autistic and neurotypical adults who receive assessments of brain structure, memory function, and intellectual ability at multiple timepoints as they age. Integrating brain imaging, genomic techniques, and statistical tools, this researcher will determine if autism risk genes also lead to memory decline and how these genes affect brain structure and the cortical thinning that is typical in all older adults. In addition, they will examine sex differences in autistic adult memory and changes in the memory system across age, with the goal of identifying sex-specific biomarkers that can be used to predict who will be most vulnerable to adverse aging outcomes. This work has implications for the future development of precision medicine and other interventions that will increase the quality of life for older adults across the spectrum.
The autism genome is comprised of genes that directly regulate protein expression and genes that indirectly regulate activity by turning on or off genes that affect protein expression. The latter genes are described as “epigenetic” and are influenced by both genetic mutations and environmental factors. What is not known is whether epigenetic mutations affect downstream processes related to autism like altering connections or function of brain cells. This project will use human induced pluripotent stem cells, or iPSCs, with a mutation of a gene called SETD1A that controls epigenetic gene regulation to examine the effects of mutations on gene expression in different types of cells. In addition, this fellow will examine how these mutations affect brain cell shape and functionality. Finally, they will investigate whether these effects are reversible, leading the way to new therapies that can help those with ASD.
Females are less likely to receive an autism diagnosis than males and several studies are examining the biological, psychological, and developmental reasons for this disparity. One theory is that language abilities and patterns in females are superior to males, possibly reflecting better social ability, which may contribute to lower diagnostic rates. This study will look at a measure of language called prosody, or the rhythm, tone and pattern used during spoken language. Studies around prosody in autistic females are lacking, mostly because there are fewer girls with an autism diagnosis who can participate in research on prosody. This fellow will examine prosody in males and females with and without autism, and compare prosody to assessments of social function and interest. These results will inform caregivers, educators, and clinicians when considering a possible autism diagnosis for girls.
Individuals with a mutation in ASH1L exhibit symptoms of profound autism, as well as several medical comorbidities. Building on this fellow’s expertise in pre-clinical models of ASH1L-related autism, the fellow will advance to a natural history study of human patients with this mutation, and their families. In addition, the fellow will collect EEG data from families and identify potential biomarkers of this gene mutation. These are critical steps that enable future drug development and seizure treatment. When the study is complete, the findings have potential to guide development of new drugs to treat symptoms of profound autism, including those with and without an ASH1L mutation.
More and more evidence is pointing to sex-related differences in gene expression as a potential explanation of the male sex bias in autism diagnosis. This study will examine the role of a gene called MYT1L that has been linked to autism. Mouse models will examine the expression of this gene in the cortex (where there is no evidence of a sex difference in expression of MYT1L) and compare it to expression in the hypothalamus (where there are sex-specific differences linked to social behaviors). The fellow will also examine social learning in males and females and count neurons to look for both behavioral and cellular changes. This will determine where in the brain sex-differential effects in social behavior originate, providing evidence for more targeted intervention strategies in males and females with autism.
Siblings have the potential to shape the developmental trajectories of individuals with autism. Early studies have shown the positive impact that a sibling can have on the outcome of an autistic brother or sister. However, these studies were unable to identify which particular aspects of being a sibling contribute most to this effect. This study will leverage existing data from about 5,000 families across multiple longitudinal studies to understand the role of a sibling in longer-term adaptive behavior, and to better identify specific factors that may influence this benefit. Findings from this research may inform intervention planning to maximize adaptive skill development across time and optimize outcomes in those with autism. The results may also provide important insight into the needs of undiagnosed siblings who may themselves need support.
Autism has a well-established and prominent 4:1 male: female bias in diagnosis, but the biological basis for this difference remains unknown. One possible theory is that the presence of estrogen may play a role in the activity of brain cells that turn neurons on or off, which is part of the “excitation/inhibition” theory in autism. To test this theory, this fellow will create different types of neurons using induced pluripotent stem cells from both males and females with autism, with and without a rare genetic variation in an autism gene called neurexin. Then, estrogen will be applied to these cells and gene expression and functioning of different cell types will be compared. This gene-by-environment study will help identify the role of estrogen during development as a component in the later biological and behavioral features of females compared to males with autism.
Recent research has implicated the gene PTCHD1 on the X chromosome as contributing to the causes of autism and intellectual disability, but there is still very little known about what it does and how it leads to changes in the brain. This project will be the first-ever attempt to determine the function of the PTCHD1 protein in its natural biological setting. Cells will be manipulated to create mutations in PTCHD1, then turned into neurons, and then the proteins that are expressed will be measured. Finally, the fellow will measure how these proteins interact in the brain. This will enhance our understanding of how this gene interacts with the rest of the brain and expand the range of therapeutic approaches intended to target specific types of dysfunction in people with autism.
Oversensitivity to touch is common in autism and can lead to discomfort and harm. In some cases, people with autism avoid other people’s touch but seek out tactile stimulation through self- stimulatory behaviors. Self-stimulation can be anything from finger tapping to headbanging, which is harmful and dangerous. While the differences in the brain’s response to different types of touch have been studied in neurotypical people, there is little information on the different responses in people with autism. This fellow will examine how the autistic brain responds to different types of touch, ultimately providing a biological basis for determining why some touch is avoided while some is sought out, which could improve therapy for dangerous self-stimulatory behaviors.
Rett Syndrome is caused by a mutation on the X chromosome at MeCP2. Girls with Rett Syndrome share many features of autism, including delayed or lack of language development, impaired fine motor skills, repetitive behaviors and cognitive disability. MeCP2 activity is also regulated by environmental factors and has been implicated in autism when a genetic cause has not been identified. This fellow will look closely at changes in MeCP2 binding and how it regulates gene expression by isolating different types of neurons at different ages to determine which are critical in the progression of symptoms. The fellow will also employ a sophisticated analysis of machine learning techniques to integrate the data to predict how MeCP2 activity regulates different neuron types at different points in development. This will allow scientists to move closer to providing patients with targeted approaches to interventions.