Autism spectrum disorders comprise a wide constellation of neurobehavioral conditions that arise from abnormal patterns of brain development. In order to understand how autism-related behaviors emerge from alterations to the normal development of the brain, it is necessary to examine how neurons differ in their patterns of connectivity among various brain regions.
Clinicians rely on a triad of behavioral characteristics for the diagnosis of autism spectrum disorders: impaired social interaction, impaired language and communication, and restricted interests and repetitive movements. However, a much broader range of behaviors has been documented in people with autism. For example, individuals with autism can discriminate slightly different grating patterns better than typically developing individuals can, but they struggle to distinguish different facial emotions.
Yehezkel Ben-Ari and his colleagues at the Institut de Neurobiologie de la Méditerranée (Inmed) in Marseille, France, showed several years ago that neurons recorded in newly born animals have elevated intracellular chloride, leading to paradoxical excitatory actions of the principal adult inhibitory transmitter gamma-aminobutyric acid (GABA)[ref]Ben-Ari Y. et al. Physiol. Rev. 87, 1215-1284 (2007) PubMed[/ref]. They showed an abrupt and brief decrease in intracellular chloride in central neurons recorded immediately after birth[ref]Tyzio R. et al. Science 314, 1788-1792 (2006) PubMed[/ref]. This shift is associated with an abrupt excitatory-to-inhibitory shift of the actions of GABA that is mediated by the hormone oxytocin, which also triggers labor.
One of the most common symptoms shared among the autism spectrum disorders (ASD) is difficulty with social interaction. Frequently, this difficulty extends to problems perceiving and producing spoken language. The neural mechanisms for perceiving speech are not well understood, so how the genetic and developmental causes of ASD give rise to this symptom is not known. Stephen Shea and his colleagues at Cold Spring Harbor Laboratory in New York are using a mouse model of ASD to help close this gap in our understanding.
Behavioral deficits observed in autism can be grouped into four clusters: physiological and neurological health; arousal, anxiety, and regulatory systems; social interaction and communication; and behavioral inflexibility and cognition. Ted Abel and his colleagues at the University of Pennsylvania are planning to characterize the phenotypes of three mouse lines engineered to model autism: mice lacking CNTNAP2 or SHANK3B and mice with a deletion of the 16p11.2 region. The researchers plan to create the strains on a C57BL6 genetic background. They also plan to analyze the 16p11.2 mice in a B6/129 F1 background, which will allow them to control for other genetic variants that might interact with genes in this region.
Autism spectrum disorders are heterogeneous neurodevelopmental syndromes characterized by repetitive behaviors and deficits in language development and social interaction. Studies in people with the disorder have implicated a number of candidate mutations, and researchers have engineered mice that harbor these genetic defects. Validation of these mouse models, however, requires detailed behavioral analyses that quantify both solitary and social behaviors.
Autism spectrum disorders represent a major cause of disability both in the U.S. and worldwide, but medical treatments are nearly nonexistent. Many major pharmaceutical companies have closed down psychiatry-related drug development programs.
Males are four to five times more likely to have autism than are females. This powerful observation implies not only that males are at greater risk, but that there may be real differences in the expression of autism between males and females. Thomas Frazier at the Cleveland Clinic Foundation and his collaborator Antonio Hardan at Stanford University in California used the Simons Simplex Collection to compare males and females with autism across a range of clinical measures. The collection is a repository of genetic samples from families that have one child with autism and unaffected parents and siblings.
Cognitive and behavioral impairments in autism spectrum disorders are thought to result from changes in the structure and function of brain circuits. Disruption of the balance between excitation and inhibition in the neocortex has been proposed as a possible mechanism. This type of imbalance could lead to altered neuronal network connections that give rise to dramatic changes in the way the brain processes information and regulates behavior.
To understand the neurobiology underlying autism spectrum disorders, more data at the cellular level are needed. This is difficult to obtain from living individuals. However, physiological data can be collected directly from cells in the human brain (i.e., neurons) during neurosurgery for medically refractory epilepsy. Two methods can be used in these cases: depth electrode recording and surface grid monitoring.