Low and high resolution images of cells from an individual with autism with fragments of accumulated beta-amyloid inside of the cells.
Jane Pickett, Ph.D., Director of Brain Resources and Data for the Autism Tissue Program
What does autism look like in a brain cell? Since the behaviors that characterize autism are an expression of brain organization and activity, it is logical to investigate this in post-mortem brain tissue’s component cells. This question was a theme at this year’s IMFAR.
The goal of brain cell research is to use information about cell organization, chemistry and genetics to inform and refine therapeutic strategies. One might assume that treatments would be only medications. However, our understanding of the activity of the brain supports behavioral therapy concepts too, especially through the involvement of a brain region known as the cerebellum. Long thought to be only involved in motor coordination, the cerebellum has lit up in functional imaging studies of language, attention and mental imagery. Jerzy Wegiel, Ph.D. at the NY Institute for Basic Research conducted a systematic study of the cerebellum’s smallest and evolutionarily oldest region, the flocculonodular lobe, which has primary connections with the brain’s balance (vestibular) and visual systems. In this region Dr. Weigel sees a disorganization among the neurons and their connections that would certainly contribute to impairment of visual-motor function.
Some of the innovative technology and training programs on display at IMFAR aimed to help children organize their visual and attention systems. Neuroscientists believe that these therapies work by engaging the brain’s remodeling abilities to correct dysfunctional connections between cells. The fact that the flocculonodular lobe is so interconnected with the vestibular system suggests that sensory integration therapies may help coordinate head and trunk movements by re-working connections in this region.
The Weigel lab also reported observing secretions of protein called beta-amyloid in brain tissue of children with autism. Interestingly, the level of beta-amyloid related to the severity of autism and aggression. The amyloid protein is a good example of nature’s multi-tasking. It is a large protein that can be cleaved to smaller active fragments depending on where and when in the brain’s development. This metabolic process may become abnormal when a particular enzyme becomes active. The enzyme is distinct from the enzymes that cleave amyloid into fragments that accumulate outside of cells in the brains of individuals with Alzheimer’s disease, where the protein is more commonly studied.
Epilepsy is a serious problem present in 39% of brain donors with autism. Autism and epilepsy is prevalent in a group of individuals with duplication of segments of chromosome 15. Children have a high rate of sudden unexpected death and the support group, IDEAS, is particularly dedicated to brain donation to the Autism Speaks’ Autism Tissue Program. Dr. Weigel and colleagues have found a broad spectrum of developmental alterations, degenerative neuronal changes and both the overproduction and activation (often a marker of inflammation) of an important brain cell type known as glia. The displacement and activation of glia as well as the appearance of clusters of neurons that appear to be immature or in the wrong place is likely to contribute to high the prevalence of epilepsy in this population.
Eric Courchesne, Ph.D. offered new revelations in brain tissue research in a dramatic keynote address that highlighted the importance of brain tissue for understanding the early abnormal post-natal growth of the brain. His lab observed more neurons in the rapidly developing frontal cortex. A closer examination of the six-layered cortex revealed differences in the unique chemical signatures that mark cells in each layer. In the brains of individuals with autism, Dr. Courchesne found that some patches of cortex do not show the expected markers. Advanced image processing devised by post-doctoral fellow Rich Stoner, Ph.D., generated a stunning three-dimensional picture of the layer, indicating that the cells are, in fact, present yet not displaying their unique signature.
Young investigators in Couchesne’s lab and others are benefitting from brain tissue resources and training in the art and science neuropathology. One such researcher, Ryan Smith, Ph.D. working in Dr. Wolfgang Sadee’s lab at Ohio State University, applied his genetics background to measure the expression of a number of genes related to synapse structure and cell-cell communication in human frontopolar cortex. Robust expression differences were observed for 11 genes between the brains of typical individuals and individuals with autism. For some genes, the genetic factors appear to be rare and only seen in brain samples from individuals with autism suggesting that rare mutations may underlie the autistic phenotype in some cases.
A central feature of the IMFAR conference was the presence of the National Database for Autism Research team leading the NIMH effort to centralize research results and make them available to the broader scientific community. Research results from brain tissue explorations of cell chemistry, cell genetics, cell metabolism, cell organization, cell-cell communication and overall brain structure are being integrated into the national database via the Autism Speaks’ Autism Tissue Program informatics portal.
The organizers of the conference gave special recognition to the parent advocates who launched the Autism Tissue Program and emphasized its ever growing importance in research. They in turn acknowledged the contribution of the families of brain and tissue donors.
