Unraveling Autism - Uderstanding Autism

Written by NIMH

Brain Tissue

Although MRI spectroscopy can perform chemical assays of structures in the living human brain, even the most advanced brain scanners cannot substitute for postmortem brain tissue. Such tissue, which has been lacking for the study of autism, offers a unique, high-resolution window into the inner workings of brain cells. For example, by using radioactive tracers on thinly sliced sections of brain tissue, scientists can detect and pinpoint any abnormal activity of genes within cells. Only with access to brain tissue can the underlying neuropathology of autism be uncovered. To take advantage of emerging opportunities for discovery in postmortem tissue made possible by the new molecular methodologies, NIMH, in collaboration with parent advocacy groups and other Institutes, is stepping up efforts to establish brain bank collections for the study of autism. For example, NIMH supports the Harvard Brain Tissue Center's ongoing efforts to collect and make this vital resource available to researchers. Such brain banks work with families to arrange for tissue donations when individuals with autism die.

Animal Models

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For obvious ethical reasons, some studies required to understand autism cannot be conducted in humans. But experiments in monkeys hold great potential, since their brains resemble those of humans. For example, NIMH-funded investigators have shown in monkeys how early injury to the brain's limbic system (hippocampus) can interfere with the establishment of social and emotional bonds. Such behavioral and neuroanatomical research may help to pinpoint brain circuit abnormalities in autism and ultimately lead to intervention strategies.

In October l998, NIMH co-sponsored, with several other NIH Institutes and two private organizations, Cure Autism Now (CAN) and the National Alliance for Autism Research (NAAR), an interdisciplinary workshop on "Building Animal Models for Autism Through Translational Neuroscience Research." This event brought together 33 scientists engaged in basic or clinical neuroscience research with scientists working on autism. They developed recommendations and identified opportunities for modeling in animals some of the neurobiological and behavioral features of autism.

For example, brain mechanisms (circuitry and chemical systems) hypoth-esized to occur in the human disorder can be experimentally approximated for study in rodent or monkey models. Some of the recommendations emerging from the conference focused on opportunities that exploit new molecular genetic approaches.

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 from among the estimated 50,000 genes that are expressed in the human brain. And even after human disease vulnerability genes are found, sophisticated tools 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 family members of people with autism may share with them an irregular segment of genetic code or a small cluster of unstable genes that produces milder, but qualitatively similar behavioral characteristics of autism. For example, they may have mild social, language or reading problems. A multi-site team of NIMH-supported investigators is studying such families to characterize these behavioral traits in hopes of discovering sites in the genome associated with them. Other investigators are screening genetic material from 350 carefully diagnosed patients with autism for possible linkage with several already known "candidate" genes. Another group is using hundreds of telltale gene markers to screen 200 families in which at least two siblings are affected with the disorder.

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 S or in the wrong place. This will interfere with the way brain cells work, migrate to other parts of the brain during early development, and make connections with one another. In collaboration with other NIH Institutes, NIMH has mounted an effort to vastly expand the set of available tools for discovering these molecular mistakes.

A vital resource for doing this, now under development, will be a shared scientific infrastructure called the BMAP (Brain Molecular Anatomy Project). The goals of this multidisciplinary effort are to catalog the genes that turn on in various parts of the brain at different developmental stages, and to make this information readily available to investigators via the Internet. This will include maps revealing a gene's locations and detailed breakdowns of its chemical components.

The mouse's brain is a major initial focus of BMAP. A Web-based digital mouse brain atlas will offer 3-D and 2-D views of this biological blueprint, covering different strains and ages of animals. A gene library of mouse brain tissue, optimized to detect rare gene variations, will speed studies of how specific genes act in both animals and humans. Studies will characterize gene expression patterns in precise brain regions in response to disease, pharmacological, or environmental influences. In addition to advancing basic knowledge, the BMAP database promises to enhance clinical science, providing new leads for studying gene expression in post-mortem tissue, for the identification of candidate genes, and enhanced capacity to screen for individuals at who might be at risk for developing brain disorders.