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Autism Tissue Program Update –

IMFAR 2009
May 13, 2009

A growing number of researchers contributed to sessions devoted to the study of the brain at this year's International Meeting for Autism Research (IMFAR).

Autism Speaks Autism Tissue Program (ATP) makes post-mortem brain tissue available to as many qualified scientists as possible to advance autism research. Using brain tissue, scientists can go far beyond the constraints of other technologies and study autism on both a cellular and molecular level. This year, conference themes of neurodevelopment, genetics and environment were reiterated in the sessions on brain tissue research.

A critical question in autism neuroscience is what is happening in brain cells during the time of rapid brain expansion from birth to later childhood and into adulthood where brain size tends to normalize. Looking strictly at neurons and their cell size relative to controls in subcortical structures, using the Autism Celloidin Library the lab of Jerzy Wegiel, Ph.D. (New York State Institute for Basic Research) and his team reported a period in early childhood (4-8 years) with markedly small neurons in many of the brain structures examined. These areas correspond to developing circuits involving behaviors such as fear, anxiety, repetition, reward and overall brain organization. No delay in neuronal cell growth was observed in the cornu Ammonis sectors 1-4, lateral geniculate body, inferior olive and nucleus of facial nerve in any age group. The current thinking is that the acceleration of brain growth from birth results in the production of immature and smaller than normal neurons that are still evident in critical subcortical areas of the young autistic brain and contributes to dysfunction in emerging circuits of brain activity.

Switching to investigations in the higher brain centers in the cortex and surveying the area of most rapid early brain growth, John Morgan, (UCSD), showed results of his work on brain tissue in his presentation on microglial cell density. Microglia are brain cells that have sparked an interest in autism due to their association with pro-inflammatory functions in the brain. Specific markers can be used to search out both activated and resting microglia, allowing measurements of cell size and relationship to other brain cells. Using a marker known as Iba-1, the researchers observed significant increases in microglial density and volume in autism in both gray and white matter. In three donors with autism under 6 years of age, the increased microglial density and volume was similar to the average older subjects suggesting that the phenomenon is present very early in autism. Moreover, as important control experiments, the researchers checked that the effects they see appear to be independent of seizure and postmortem interval, to factors which have made it difficult to interpret previous research with postmortem tissue. At this stage of study, it is not possible to distinguish whether the presence of activated microglia are a cause or reaction to the processes that drive autism.

Another approach to the question of brain changes representing inflammatory processes was discussed by Arun K. Azhagiri, Ph.D. (Johns Hopkins Univ.). His study investigated toll-like receptors (TLRs) in four brain regions of autistic and unaffected brain donors. TLRs are associated with the initiation and regulation of the innate immune response to pathogens like bacteria or viruses. At least 10 TLRs have been demonstrated in humans and some are expressed in neurons, astrocytes, and microglia in the central nervous system. Immunocytochemical studies demonstrated that TLR-2 and TLR-3 was localized in astrocytes and microglia cells and TLR-4 was observed mostly in microglial cells. The major place TLR signaling gene expression changes occurred was in the anterior cingulated gyrus, ACG, a brain site of interest linked to social/behavioral changes in autism. It is thought that the gene expression changes in the ACG reflect the status of neuroimmune activation in selected regions of the cerebral cortex and concurs with observations of increased innate neuroimmune and neuroglia responses in autism. In addition, two down-regulated genes in the MFG (SARM1 and UBE2N) were also associated with regulation of the number of neurons. Further work on these and other genes governing cell growth and development, in more brains and in more regions, will be necessary to pin down the role of gene pathways mediating disease response in the brain of young autistic children.

Leading a session on neuropathology was Gene Blatt, Ph.D. (Boston Univ. School of Medicine). He reviewed work in his lab on brain cell neurochemistry in his talk. Pointing out that the GABA inhibitory neurotransmitter system alterations have emerged as a consistent neuropathological finding in autism, he focused on the ideal brain region to study these changes; the cerebellum, Looking specifically in the posterior lateral cerebellar cortex, he reported the density/number of GABA receptors (GABAAR, GABABR and benzodiazepine binding sites) was altered in adult autism subjects. This finding was interesting in light of other reports that changes in expression of the enzymes that synthesize GABA have been found in inhibitory neurons in the cerebellar cortex and in other regions of the cerebellum, potentially reflecting changes in inhibitory neurotransmission within the cerebellumcircuits. Overall, a number of key GABA biomarkers have emerged suggesting a cascade of events might lead to abnormal cerebeller circuitry in adults with autism.

A second report from this lab was given by Adrian Oblak, (Boston Univ. School of Medicine) who asked whether receptor neurochemistry could resolve the question of what is happening in the fusiform gyrus (FFG), a key area in face identification and processing that has been shown to function abnormally in autism. Brain imaging studies have been contradictory, with some showing that patients with autism are capable of performing face perception tasks while others find the FFG to underactivate. Here the researchers looked at two neurotransmitter systems, GABA and serotonin (5HT), and found that GABAB receptor density and BZD binding site density were shown to be significantly decreased in the superficial layers in autistic cases. In the deep layers there was a significant decrease in the density of GABAB receptors, but no change in BZD binding site density. Additionally, there were significant reductions in the density of 5HT1A receptors in both the superficial and deep layers in autistic cases. The abnormalities in the superficial layers suggest a disruption in cortiocortical connections and changes in the deep layers suggest altered connectivity to sub-cortical regions.

It is helpful to consider these two studies together. They provide more evidence of GABA alterations in the hippocampus, anterior and posterior cingulate cortex and FFG reflecting what appear to be altered inhibitory circuits in the brain. The second study, focusing mainly on the FFG region provides more detailed evidence of abnormalities in the GABAergic and serotonergic receptor systems, which may contribute to abnormal face processing in individuals with autism where face perception is an elemental part of the social experience of recognizing persons and expressions.

Of the numerous brain research posters and presentations, reflecting the increased interest in research on brain tissue, another is worth mentioning in view of the role of serotonin in autism. A study by Efrain Azmitia, Ph.D. (New York Univ.), used brain tissue to investigate reports of PET scans of living subjects – boys with autism aged 2-5 – which showed lower serotonin in the frontal cortex and thalamus than in control subjects. Early results on limited brain samples show serotonergic axons in the medial forebrain bundle, septum and preoptic area are increased in autism compared to typical controls, while axons in temporal cortex and hippocampus are reduced at all ages studied. Abnormal serotonin-containing fibers were seen in amygdala and temporal cortex in the brains from older autistic patients (12-29 yrs.). In temporal cortex of autism donors, astrocytes are reactive at all ages while microglial cells are reactive only at the youngest age.

In sum, this precious resource continues to prove its value in evaluating brain changes across the lifespan. The cumulative brain tissue reports this year sum up the contributions of over 20 researchers who investigated various genes, gene products, gene pathways, and various cell types, in more and more brain regions, in brain donors of all ages. Brain development, especially in the youngest with autism, has altered course in almost every case. Working in an interdisciplinary manner was the theme many IMFAR presentations; one notably by Declan Murphy, M.D. (King's College London), who encouraged the field of brain imaging to build on neuropathological findings (and the reverse situation where neuroimaging guides pathology). In a perfect world, these technologies and the fields of genetics and immunology will inform each other on a regular basis and help find the mechanisms involved in regulating synaptic/dendritic organization and the cell circuits that generate the behaviors we know as autism. Then we have the potential to isolate targets for treatment.