Autism Spectrum Disorders Research at NIMH, Page 4
This overview summarizes research into the causes, diagnosis, prevention, and treatment of autism spectrum disorders.
Developmental Neurobiology
To function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process, resulting in circuitry gone awry, are hypothesized to occur in neuro-developmental disorders like autism. NIMH-funded researchers recently developed a way to discover the normal wiring diagram of the mammalian brain.35 The technique, a type of “gene trap,” provides a shortcut for identifying from among the tangled trillions of neural connections just the machinery involved in brain wiring. The trick for finding the needle in a haystack: attach a molecular tag to the needle. Through genetic engineering, lines of mice are bred to express telltale mutations. Brain neurons harboring particular wiring molecules are revealed by a blue tint, while their tentacle-like extensions, or axons, are colored purple.
By breeding strains of mice in which particular genes are knocked-out, other Institute-funded researchers have been discovering the molecular machinery of the guidance systems used by such migrating embryonic neurons. When they knocked-out the cell’s antennae for receiving vital signals from guidance chemicals, the tentacle-like axons failed to make the proper connections.36
After reviewing evidence pointing to abnormal brain development in autism, researchers at the University of California, supported in part by NIMH, have proposed that the disorder stems from mechanisms gone awry that normally regulate brain growth. This “growth dysregulation hypothesis” holds that the anatomical abnormalities seen in autism are caused by genetic defects in brain growth factors. Due to abnormal timing in the starting and stopping of growth in neurons and supportive tissue, there is premature overgrowth in some brain structures and reduced growth or excessive cell loss in others, the researchers suggest.37 Although the head size and brains of children with autism are slightly smaller than normal at birth, they undergo a spurt of excessive brain growth soon thereafter. Increased head circumference by the end of the first year predicted an enlarged cerebrum and cerebellum by 2 to 5 years of age. Sudden, rapid head growth in an infant may signal for risk of developing autism, the researchers propose.38
Neuropsychology
NIMH-supported neuropsychologists are dissecting the nature of cognitive deficits in autism and related disorders. Since identification of the syndrome more than 60 years ago, clinicians and researchers have been intrigued with the uneven ability profiles of individuals with autism. While many affected individuals show generalized deficits, many also show areas of intact functioning. The nature of these deficits and strengths, their relationship to clinical symptoms, implications for treatment, and implications for underlying neurobiology, are the focus of these studies.
Adults with autism show more executive function deficits than those with other developmental disabilities. Executive functions include the ability to plan ahead, work toward a goal and to hold a mental representation “on-line” in working memory. To see if such deficits might underlie the syndrome, NIMH-funded researchers at the University of Denver compared the performance of preschoolers with autism with age-matched controls on eight executive function tasks. Surprisingly, the children with autism performed as well or better than the control group, suggesting that developmental lags in this area are not specific to autism. A second study that tracked children’s progress in performing a spatial reversal task over a year found no evidence that children with autism were growing into an executive deficit over time. Rather, the children without autism seemed to be growing out of a deficit. The two groups seemed to be on diverging developmental trajectories. These results cast doubt on the notion that autism stems exclusively from executive function deficits.39
Co-occurring Disorders
In addition to cognitive impairments, individuals with autism and other ASDs often suffer from multiple and severe mental and emotional problems. These include impulse-control disorders, obsessive-compulsive disorder, mood and anxiety disorders, mental retardation, and genetic disorders such as Fragile X. Such co-existing problems start early in life, are chronic, and account for a substantial portion of outpatient, inpatient and residential services. They present immense challenges to clinicians and families, and the complexity of the psychopathology presents enormous research challenges. NIMH is developing and testing treatment and rehabilitative interventions for such co-occurring psychopathology.40 Individuals with autism may also have co-occurring seizures and tuberous sclerosis, a genetic disorder that causes benign tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs.
A key set of proteins involved in synaptic plasticity and neuronal growth, some of them likely implicated in ASDs, has been discovered by an NIMH-funded scientific team. Researchers at the University of Pennsylvania and the University of Illinois developed a new technique that revealed, in living neurons, a swath of secondary damage caused by the primary protein defect in Fragile X syndrome, the most common inherited form of mental retardation. Mental retardation is common in people with autism, and the new findings suggest that ASDs too may be traceable to this protein pathway. Gene knockout mice modeling the protein defect showed abnormalities in the distribution and quantities of some of the affected secondary proteins and the genetic material that makes them. A melding of genomics and proteomics, the new method, called Antibody Positioned RNA Amplification (APRA), can be applied in similar studies of other systems and cells.41
Defective fragile X mental retardation protein (FMRP) can have devastating effects because as an “RNA binding protein” it influences many other proteins in critical brain centers, like the hippocampus, a memory hub. FMRP regulates the synthesis and transport of a bevy of here to fore unknown associated proteins. Like a dispatcher in a truck depot, FMRP manages the shuttling of these “cargo proteins” from the cell’s nucleus to supply the needs of its working parts, or cytoplasm. Much of the cargo turns out to be the genetic material (RNA) that makes proteins vital to synaptic maturation and communication between neurons which breaks down if the ‘dispatcher’ can’t do its job.
To discover FMRP’s cargo proteins in cultured mouse hippocampal neurons, the researchers devised an intricate methodology (APRA) that takes advantage of the specific affinity that antibodies and short strands of genetic material have for particular genes and proteins. They joined an antibody that binds to FMRP with genetic material that, in turn, binds to genes associated with FMRP. The antibody positions the molecular probe close to the FMRP cargo so that it can be detected. Among genes expressed in the human brain, about 60 percent detected by the probe were directly associated with FMRP again, many involved in synaptic plasticity and neuronal maturation.
Since some people with Fragile X syndrome show autistic behavior, the researchers suspected that some FMRP cargo proteins might also be associated with autism. Among the 81 proteins, 15 mapped to the same chromosomal locations as candidate autism genes. Mutations in some of the genes that code for these proteins may contribute to autism and other disorders characterized by autistic-like social impairment and stereotyped behavior.
