Progress in autism brain tissue research was exhibited prominently last month in Washington, D.C. at the 37th annual Society for Neuroscience (SFN) meeting. Among the themes presented at the SFN were the efforts of scientists
that utilize donated neurological tissue from individuals diagnosed within the autistic spectrum. Basic research of post-mortem brain tissue is one of the few ways to reveal direct information on the biological processes occurring within the brain of individuals with autism. This research could not be done without the courageous acts of brain donation made by family members of loved ones with autism who have passed. After touring these presentations and speaking with these researchers, the new director of the Autism Tissue Program (ATP), Daniel Lightfoot, Ph.D., reported that "…it was incredibly inspiring to see the efforts of young researchers seeking to elucidate the cellular and molecular mechanisms that contribute to autism. Even more impressive, was the high level of stewardship and the amount of research achieved by these scientists that were given such limited quantities of this most rare of tissues."
During the conference, several brain tissue projects focused on changes found in specific genes whose functions are important in brain development and function. All of this was made possible by donors who sought to make a difference in the fight to understand autism.
Christina Muratore, a doctoral candidate in the lab of Richard Deth, Ph.D., at Northeastern University in Boston, led research probing levels of methionine synthase (MS), an enzyme that promotes a chemical reaction called methylation, which is important for synthesis of the antioxidant glutathione (GSH). Her research showed that normal brain tissue levels of MS mRNA significantly decreased with age. Interestingly, autism-associated samples, particularly at younger ages, exhibited an initial low level of MS mRNA when compared to normal tissue. These results suggest that autism is linked with a decreased level of MS activity during early years of development. Reduced levels of MS in the autistic brain may be suggestive of an adaptive response to neuroinflammation. Currently, GSH levels are being measured in clinics studying blood and urinary metabolites of patients with autism, granting a great opportunity to link both basic brain research and clinical studies together.
A group led by Daniel Campbell, Ph.D., at Vanderbilt University, focused on the MET tyrosine kinase receptor gene in patients with both autism and chronic gastrointestinal (GI) dysfunction. Because the MET gene encodes an enzyme that is known to function in both brain development and GI repair, the investigators hypothesized that an association of the autism-associated MET variant may be enriched in a subset of individuals with co-occurring autism and GI symptoms. This team has previously shown that the gene activity and protein expression of a particular variant of MET were significantly decreased in individuals with autism as compared to unaffected donors. Their new results presented at the conference showed that their gene target, the MET 'C' allele, was indeed associated with both autism and GI symptoms. These results suggest that disrupted MET signaling may contribute to both brain-based and systemic dysfunctions that are observed in a subset of individuals with autism, and may provide increased sensitivity in stratification of children with autism into unique subgroups for improved treatment.
Leading a group of researchers in Rome, Tony Persico, M.D., looked at genes associated with autism, their copy number and the resulting amount of gene products (the greater the number of copies, the greater the amount of gene product) produced within brain cells in a small sample of patients. Their research found that this copy number variation (CNV) and the resultant expression level of genes that are linked to autism, surprisingly displayed little or no correlation to the state of the autistic brain, but has revealed interesting changes in genes belonging to immune pathways. It will be very important to follow up on this line of inquiry especially since there are specific CNV disorders where autism manifests at a high rate (85%).
Research carried out by Gene Blatt, Ph.D., at Boston University School of Medicine, has shed new light on the neural circuitry of two brain regions significant to autism – the cerebellum and cingulate gyrus. His lab showed results of a new study on Von Economo Neurons (VENs), which are specialized brain cells unique to humans and higher primates that populate a region of the brain known as the anterior cingulate gyrus. It is thought that VENs have many functions ranging from relaying input related to 'fast intuitive assessment of complex situations', to theory of mind, and may even contribute to socioemotional and higher-order cognitive processing. Study of the autistic brains revealed a significant increase in VENs in layer V (main output of cortex) of the brain. Other members of his lab have been exploring the cellular and molecular explanation for the proven clinical approach of Selective Serotonin Reuptake Inhibitor (SSRI) treatments in caring for individuals with autism. Evaluating serotonin receptors within the cingulate cortex, she found a significant decrease in the density of two serotonin receptors. These findings may help elucidate the biological mechanism of how SSRI treatment works in autism and allow for more targeted treatments to be designed.
ATP Tissue Advisory Board Approves Two New Projects
During the SFN conference, the ATP Tissue Advisory Board formally met and approved two new projects that are delving into molecular neuropathology in order to describe altered biochemical pathways that can serve as therapeutic targets. Prof. Paul Harrison, Ph.D., at Oxford University will study D-amino acid oxidase (DAO) – an enzyme that metabolizes the NMDA glutamate receptor co-agonist D-serine. DAO has been implicated in the pathophysiology and genetic etiology characteristic to schizophrenia. Glutamate neurotransmission via NMDA receptors is a critical player in neurodevelopment, synaptic plasticity, and cognition. As such, the regulation and status of NMDA receptors is an important factor to consider in all psychiatric disorders that include (or are thought to include) these processes. Finally, epigenetic regulation – the reversible regulation of various genomic functions occurring independently of the DNA sequence – has been an area of genetic research that has received increasing attention within the field of autism. Patrick Johnston, Ph.D., at the Institute of Psychiatry at King's College in London, plans to study epigenetics by conducting genome-wide DNA methylation analyses on autism tissue. Once identified, methylation differences can then be correlated with changes in gene expression, granting a clearer picture of brain tissue epigenetics in the autistic brain. Again, this research could lead to new directions in therapeutic possibilities addressing the biological issues at the core of autism.
To find out more about Autism Speaks' Autism Tissue Program, visit the ATP page here.