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Important Progress Made in Autism Brain Tissue Research

Autism Tissue Program Scientists Present Exciting Research Findings at the 2007 Society for Neuroscience Annual Conference
November 28, 2007

A few short years ago, research presentations on autism at the Society for Neuroscience (SfN) were sparse. At the SfN conference this month, with over 31,000 neuroscience attendees, rows and rows of posters were displayed with compelling research findings on

cell biology, the impact of brain chemicals, genetics, and the immune system which all contribute to our understanding of the causes of autism and pave the way to treatment interventions. The findings submitted here are samples of the important progress made in autism brain tissue research.

Decreased 5HT2a receptor binding density in the posterior cingulate cortex (BA 23) in autism

Adrian Oblak, Sandy Thevarkunnel, and Gene J. Blatt

Department of Anatomy and Neurobiology, Boston University School of Medicine

Previous brain imaging and post-mortem tissue studies have demonstrated abnormal neuroanatomical changes in people with autism. This study investigated the role of serotonin (a neurotransmitter believed to play a role in the regulation of mood, anger, aggression, sleep body temperature and appetite) and the posterior cingulate cortex (PCC) which normally modulates social and emotional behavior by responding appropriately to emotional scripts and faces. Common autism characteristics include diminished eye gaze fixation, lack of social and emotional reciprocity, and the failure to develop age-appropriate peer relationships. The posterior cingulate cortex (PCC) is activated when normal subjects see faces or hear voices of emotionally significant people in their lives; however, in autism the level of activation is impaired.

Alterations in cortical serotonin (5-HT) may in part underlie the neuroanatomic and social behavioral abnormalities reported in autism. The use of selective serotonin reuptake inhibitor (SSRI) medication has been shown to be successful in the treatment of autistic behaviors in some individuals. Serotonin (5-HT) has a role in neuronal development and has been extensively studied in autism with reports of excess 5-HT in the blood (hyperserotonemia) in some people with autism. Serotonin studies in the brain, however, are less frequent. This study was undertaken to see if brain abnormalities also exist.

The results show that there was a significant decrease in the density of one key type of serotonin receptor, the 5HT2A receptor, in the superficial cortical layers of the PCC in the adult autistic group when compared to age-matched controls. Similar results were found recently in the anterior cingulate cortex, an area involved in social-emotional processing. Evaluated together, these findings suggest that the 5-HT2a serotonin receptor decrease occurs in widespread cortical areas and may play a central role in some of the social deficits observed in autism.

Decreased levels of brain-derived neurotrophic factor (BDNF) in the cerebellum of patients with autism

Jane Yip, Adrian Oblak and Gene J. Blatt

Department of Anatomy and Neurobiology, Boston University School of Medicine

Neurotrophins are a family of proteins that encourages the survival of neurons. A major neurotrophin, brain-derived neurotrophic factor (BDNF), is a protein found in the brain that plays a significant role in long-term neuronal development and survival. There is compelling evidence that led to the hypothesis of a role of BDNF in the development of autism including increased serum concentrations of BDNF in children with autism and identification of different forms of BDNF in families of autistic individuals. The cerebellum was targeted in this study, since pathological differences in the cerebellum in people with autism have been widely reported and recently, in mutant mice, cerebellar deficits have been associated with reduced neurotrophin release.

In this study the regulation of BDNF in the cerebellum of six autistic patients and six controls was studied by measuring the protein level of BDNF in post mortem tissues. The level of BDNF was significantly decreased in the autistic group compared to controls. Reduced BDNF in the cerebellum may be an indicator of aberrant brain development and growth in autism.

Further research to understand the reason for these reduced levels is the prerequisite for effective treatment models.

Microglial activation in a 3 year old autistic brain

John T. Morgan, G. Chana, J. Buckwalter, E. Courchesne and I.P. Everall
University of California, San Diego

Several previous studies have suggested that there might be immune system alterations in the developing or adult brains of people with autism. In this study, researchers examined postmortem brain tissue to look for abnormalities in microglia, a type of immune cell that absorbs and engulfs waste materials. Using a relatively new staining technique, researchers found an increase in the density of microglia. In addition, the shape of the microglia was significantly altered such that the cells appeared similar to activated (inflamed) microglia in a number of other systems.

The fact that these changes in cellular appearance and increase in cell density were present in brains as young as 3 years of age suggests that alterations in microglial function and number are one factor of the early brain growth pattern of people with autism. Increases were also observed in adults, suggesting that these alterations may persist over time. Similar qualitative changes in microglial shape were observed across several brain structures suggesting that these changes are unlikely to be solely a cellular stress response to the increased frontal cortical growth observed in the developing brains of many people with autism.

Caution is urged in interpreting the findings. Microglial alterations were not observed in every person with autism, only a significant majority. Additionally, it is unclear whether these glial alterations actually reflect inflammatory processes, post mortem (cause of death) effects or a neuroprotective response to increased excitatory neurotransmission. If they do reflect inflammatory processes, it is not clear whether they might be responding to external environmental triggers, internal environmental challenges (such as an increase in other cell numbers) or alterations in the genetic immune system. It is also unclear whether any neuroinflammatory processes would be at a level substantial enough to interfere with brain function. Further research is needed to clarify these questions.

PRKCB1 and autism: reduced gene expression in the temporal cortex of autistic brains, and significant association between PRKCB1 gene variants and autistic disorder

A. M. Persico, C. Lintas, R. Sacco, L. Gaita, R. D'oronzio, K. Garbett, K. Mirnics, R. Militerni, C. Bravaccio, P. Curatolo, B. Manzi, C. Schneider, R. Melmed, M. Elia, T.Pascucci, S. Puglisi-Allegra and K. Reichelt

Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy

This study (as well as the following two studies described below) is the result of a longstanding collaboration between Dr. Persico and investigators in Rome, Italy, and colleagues in other countries and the U.S. In this study, Dr. Persico examined the PRKCB1 gene in gray matter brain tissue samples of eleven autistic patients with age and sex matched controls. PRKCB1 gene differences were previously found associated with autism in a genome-wide linkage scan in 116 families from the AGRE DNA collection and an independent replication of the association in a second set of 167 trio (mother-father-child) families with autism. This gene plays an important role in signal transduction, the process by which a cell converts one type of signal into another. It also controls cell division, differentiation and gene expression (the process in which the inheritable information in a gene such as the DNA sequence is made into a functional gene product, such as protein).

Using a technique called microarray analysis, the activity of the PRKCB1 gene was found to be reduced on average by 26% in six post-mortem autistic specimens compared to six matched controls (with 7 out of 11 autistic patients showing lower mRNA (messenger RNA) levels compared to their matched control), and with the remaining 4 patients showing comparable levels. Finally, the protein made by this gene was decreased in 7 out of 8 patients compared to their matched control.

This study demonstrates how brain tissue analysis assists in identifying genes that are altered in some donors with autism. These findings further validate the genetic association between autism and PRKCB1 gene variants and further indicate that PRKCB1 gene expression is decreased in the brain of a significant subgroup of autistic individuals. Knowing the genes associated with autism assists in genetic testing and interventions that would possibly correct the imbalance of the gene product (the protein they measured).

Immune transcript disturbances in temporal cortex of autistic brains

K. A. Garbett, P. Ebert1, C. Lintas, K. Mirnics and A. M. Persico
Psychiatry, Kennedy Center for Human Development, Vanderbilt University, Nashville, TN

Since autism is considered to be a result of complex interactions of genetic, environmental and immunological factors, Garbett and colleagues wanted to understand the molecular events occurring in brains of autistic individuals. Garbett described the global transcriptome changes (transfer of genetic information from the DNA molecule to the messenger RNA) in temporal cortical tissue from the postmortem brains of autistic individuals. Using DNA microanalyses, they found significant changes in 20+ selected genes in six autistic brains compared to age and gender matched healthy controls.

Further analysis of a subset of genes revealed that they were identified as immune system-associated and may impact cell-cell communication, the behavior of cells, and regulation of cell growth. Many of the genes in this subgroup are known to be directly or indirectly regulated by cytokines (a chemical signaling compound, similar to hormones and neurotransmitters which are especially important in immune response). The study hypothesized that if the changes are related to cytokine production, it may represent the reaction of autistic brains to either environmental triggers or to antigens within one's own tissue which leads to enhanced and prolonged immune system activation.

Reelin Gene expression and promoter methylation status in temporal cortex of autistic brains

C. Lintas, V. Papaleo, K. Garbett, K. Mirnics and A. M. Persico
Lab. Mol Psychiat & Neurogen, Univ. Campus Bio-Medico, Rome, Italy; IRCCS "Fondazione S.Lucia", Rome, Italy

Reelin, a protein found primarily in the brain, has a critical role in neurodevelopment and has been implicated in autism, schizophrenia and bipolar disorder. Past studies have shown that the amount of methyl groups attached to the gene (RELN) alters the amount of gene product as measured by the messenger RNA that makes the protein, reelin. This is significant since variation in gene expression plays a major role in the development of many diseases – Rett disorder, a pervasive developmental disorder in the same category as autism, is a classic example. Previous studies of post mortem brains of schizophrenic and bipolar disorder patients have shown that the methylation status of the reelin gene is highly elevated. In this study, reelin and methylation status were assessed in the gray matter brain tissue samples of six autistic patients and sex-, age-matched controls. They found that post pubertal autistic patients had increased methylation in certain regions as compared to their matched controls and reelin gene expression was reduced in this older group of brain donors. Age-related findings are becoming common in autism brain research and may help us understand how the control of the genome changes over time. These results are being replicated in additional pairs of patient and control brain tissues.

Early growth response gene 2 (Egr2) is dysregulated in autism and Rett syndrome brain

S. E. Swanberg, R. P. Nagarajan, J. M. Lasalle
Univ. California Davis, Davis, CA

Understanding the specific causes of autism has been difficult to determine due to the likely complex interaction between genetics and environmental triggers with many genes making small contributions to the phenotype. This study focused on the Early Growth Response genes which are members of a complex regulatory pathway which influences the development and maturation of neurons. One Early Growth Response gene (Egr2) plays an important role in early embryonic development of the brain. This early developmental pattern impacts neuronal networks which control mature brain function. For example, the majority of neurons that make serotonin and are exquisitely sensitive to environmental factors, arise from the embryonic hindbrain. Changes in these neurons may be one factor in the cause of autism and certain psychiatric disorders. EGR2 is also expressed throughout the later prenatal and postnatal periods in areas of the brain including the cortex, brainstem and cerebellum and may be involved in the development of neuronal connections and maintenance of nerve conductivity.

Rett syndrome (RTT) is an X-linked disorder caused by MECP2 mutations or expression defects and is one of the only autism-spectrum disorders with a known genetic cause. MeCP2 is required for maturation of neurons. Previous studies have shown MeCP2 mutations or expression defects are found not only in Rett's but are also observed in a subset of autism-spectrum cases. In this study, postmortem tissue was examined using chemical analysis and laser scanning. Statistically significant decreases in Egr2 expression were found in both RTT and autism cortical cells compared to the typically developed controls. Egr2, a potential MeCP2 target and autism candidate gene, is changed in Rett's and autism. Knowledge of specific genes associated with pervasive developmental disorders will help clarify the roles of these genes and assist with specificity of future genetic testing.

Differential methylation of the gene encoding myo-inositol synthase in rat and human tissues: implications for autism

R. S. Seelan, J. Lakshmanan, M. F. Casanova, R. N. Parthasarathy
University of Louisville, Louisville, KY

The impact of methylation (a chemical change where the addition of a methyl group occurs) on a gene is assessed in this study of the methylation status of the gene encoding enzyme, myo-inositol synthase. In rats the gene is called Isyna1 and the human gene is called ISYNA1. Myo-inositol is a major component in a particular type of signaling pathway that activates a number of neurotransmitters and messengers. Brain myo-inositol levels have been found to be significantly depleted in autism spectrum disorders. Furthermore, the gene ISYNA1 is located in an autism susceptibility site, 19p13.1 (chromosome 19, short arm (p) in the region defined as 13.1).

The authors mention that these observations make the ISYNA1 gene an attractive candidate for control by methylation. Their results suggest that gene methylation may account, in part, for the differential expression of myo-inositol synthase mRNA in various tissues. They indicate that "it is possible that the methylation patterns, carefully set during fetal development, are more affected in the male brain when subjected to certain environmental insults. Such gene methylation profiles could serve as blueprints for identifying salient methylation changes that may occur in autism and other behavioral disorders".