Autism Spectrum Disorders Research at NIMH, Page 3
This overview summarizes research into the causes, diagnosis, prevention, and treatment of autism spectrum disorders.
Animal Models
Studies in monkeys hold great potential for understanding autism, since their brains resemble those of humans thus offering valuable clues. For example, NIMH-funded investigators are continuing to examine monkeys in which early injury to the brain’s limbic system, or emotional hub, interfered with the establishment of social and emotional bonds.25 Experiments in monkeys by NIMH intramural scientists found that loss in infancy of two key limbic structures, the amygdala and hippocampus, results in social and emotional abnormalities strikingly similar to autism, in both nature and time course, by 6 months of age. The monkeys with brain lesions, like some autistic children, showed an absence of social interactions, lack of normal facial expressions and body language, and stereotyped behaviors. Also as in autism, the problems emerged only after early infancy and remained permanent. Other monkeys in which a lower part of the temporal lobe was removed developed milder symptoms that substantially abated as they grew older. This study, combined with clinical findings, point to the limbic system structures as likely sites of damage in autism.26 Such behavioral and neuroanatomical research may help to pinpoint brain circuit abnormalities in autism and ultimately lead to intervention strategies. Findings relevant to autism may also emerge from planned studies of proteins in the animal brain.
Assuming there is a developmental abnormality in autism, due to a gene defect or gene/ environment interaction, some genes are likely to turn on too much or too little or in the wrong place. This may interfere with the migration and wiring of embryonic brain cells during early development, or with the way cells function. In collaboration with other NIH Institutes and the private sector, NIMH is mounting efforts to expand the set of available tools for discovering such molecular mistakes.
For example, studies in mice are identifying the neural basis of complex behaviors. The mouse has become a critical model in studying human disease because scientists have access to many specially bred strains each expressing distinctive physiological and behavioral characteristics and know an enormous amount about mouse genetics. Rapidly-evolving technologies now make it possible to insert, knock out, or mutate mouse genes, quickly breed a generation that expresses the change, and then see how it affects behavior. When autism-linked genes are discovered, they will be inserted and expressed in mice to find out what they do at the molecular, cellular, and behavioral levels. Researchers will be able to track a wiring abnormality, a cell migration abnormality, or other anomaly that may lead to symptoms in humans.
Clinical Genetics
While it is known that heredity plays a major role in complex behavioral disorders like autism, the identification of specific genes that confer vulnerability to such disorders has proven extremely difficult. Detecting multiple genes, each contributing only a small effect, requires large sample sizes and powerful technologies that can associate genetic variations with disease and pinpoint candidate genes. And even after human disease vulnerability genes are found, sophisticated techniques will be needed to find out what turns them on, what brain components they code for, and how they affect behavior. Although by no means assured, the prospect of acquiring such molecular knowledge holds great hope for the engineering of new therapies.
Evidence suggests that some family members of people with autism may share with them milder, but qualitatively similar, behavioral characteristics of autism.27 For example, they may have mild social, language or reading problems. A multi-site team of NIMH-supported investigators has been studying such families to characterize these behavioral traits in hopes of discovering sites in the genome associated with them. In the latest phase of these studies, neuropsychological characteristics of relatives of individuals with autism and autism spectrum will be compared with those of people with injuries to brain areas implicated in autism, such as the amygdala and frontal cortex. Patterns of co-occurrence of the characteristics will be examined in individuals and families.28
Four previously undetected chromosomal sites strongly linked to autism have been discovered by the largest and methodologically most sophisticated genome-wide screens to date, funded, in part, by NIMH. Two studies, led by investigators at Columbia University and the University of Oxford, add regions on chromosomes 2, 5, 8, and 17 to a growing list of areas likely harboring autism-predisposing genes. They also add to previous evidence implicating areas on chromosomes 7, 16 and 19.29,30
Although one chromosomal region, 7q, had turned up consistently in such screens, no specific candidate gene there had yet been pinpointed until NIMH-funded researchers, led by a team at the University of Iowa, discovered that variants of a particular gene in the 7q region, expressed in human thalamus, may be associated with autism susceptibility.31 It is a member of a family of genes that influences brain development.
To increase the likelihood of finding genes for autism, researchers are increasing the statistical power of human data sets. One genome-wide screen of autism vulnerability genes in 110 families showed suggestive evidence for linkage to ASD on several chromosomes. In a follow-up analysis, the researchers increased the sample size threefold while holding the study design constant, so that 345 families (each with at least two siblings affected with autism or ASD), were included. The most significant findings were on chromosome 17q conspicuously near the gene that codes for the serotonin transporter and on 5p.
Analyses from this largest data set studied to date implicate brain serotonin systems in autism. This finding is congruent with those from other studies which show evidence of elevated blood serotonin levels both in patients with autism and in their unaffected first-degree relatives. Studies also show that drugs that selectively target 5-HTT can ameliorate some autism-related symptoms. Serotonin-related neural circuits may thus provide targets for new drug development.32
Continued progress in molecular genetic studies of autism will require very large sample sizes, and the pooling of ever larger numbers of families. In addition, future studies likely will require the identification and characterization of autism-related traits correlated with liability to produce disease. NIMH is supporting efforts to reach out to families to build a library of DNA samples and clinical data that can be broadly distributed to researchers through the NIMH Human Genetics Initiative. For example, in March of 2002 NIMH announced the awarding of a grant totaling more than $6 million, over five years, to researchers at the University of California, Los Angeles, for a major expansion of the Autism Genetic Resource Exchange (AGRE) gene bank, a collaborative effort with the citizens group Cure Autism Now (CAN). The goal is to add 300 more families to this resource, which conducts 2-hour in-home screenings of families that have more than one member diagnosed with autism, PDD or Asperger’s syndrome.33 A similarly ambitious $5 million public/private collaboration between the National Alliance for Autism Research (NAAR) and NIMH, NICHD, NINDS, NIDCD was recently announced. The NAAR Autism Genome Project is also focused on finding genes associated with the autism spectrum disorders.
Using the AGRE data set, researchers at Rutgers University recently discovered a strong association between a gene in the 7q region and autism. Among 167 affected families, children with autism were twice as likely as unaffected children to have inherited a particular variant of a gene called ENGRAILED 2. The team is now attempting to replicate the finding in a much larger sample, using NIMH-funded data sets funded in part by NIMH.34
