The Neurobiology of Autism

Abstract

Improving clinical tests are allowing us to more precisely classify autism spectrum disorders and diagnose them at earlier ages. This raises the possibility of earlier and potentially more effective therapeutic interventions. To fully capitalize on this opportunity, however, will require better understanding of the neurobiological changes underlying this devastating group of developmental disorders. It is becoming clear that the normal trajectory of neurodevelopment is altered in autism, with aberrations in brain growth, neuronal patterning and cortical connectivity. Changes to the structure and function of synapses and dendrites have also been strongly implicated in the pathology of autism by morphological, genetic and animal modeling studies. Finally, environmental factors are likely to interact with the underlying genetic profile, and foster the clinical heterogeneity seen in autism spectrum disorders. In this review we attempt to link the molecular pathways altered in autism to the neurodevelopmental and clinical changes that characterize the disease. We focus on signaling molecules such as neurotrophin, Reelin, PTEN and hepatocyte growth factor, neurotransmitters such as serotonin and glutamate, and synaptic proteins such as neurexin, SHANK and neuroligin. We also discuss evidence implicating oxidative stress, neuroglial activation and neuroimmunity in autism. Pathol 2007;17:434-447. Brain INTRODUCTIONAutism spectrum disorders (ASD) are the most devastating conditions in the broad range of developmental abnormalities known as "pervasive developmental disorders" (175). ASD comprise a complex and heterogeneous group of conditions that include autism, Rett and Asperger syndromes, and pervasive developmental disorder-otherwise nonspecified (2). The main clinical features of ASD are stereotypic behaviors and marked impairment in communication, social skills and cognition (129,174). Clinical signs of ASD are frequently present at 3 years of age and recent prospective studies in toddlers indicate that abnormalities in social, communication and play behavior that may represent early indicators of autism can be detected as early as 14 months of age (124). Abnormalities in language development, mental retardation and epilepsy are frequent problems in the clinical profiles of patients with autism, and some patients may exhibit features of clinical regression, in which neurodevelopmental milestones are lost and/ or other clinical signs worsen (174). ASD are clinically heterogeneous and can be associated in up to 10% of patients with well-described neurological and genetic disorders, such as tuberous sclerosis, fragile X, Rett's and Down syndromes, although in most patients the causes are still unknown (159, 176) (see review by London). The heterogeneity and clinical variability of autism has prompted some researchers to use the term autisms instead of autism (81).The stereotypic behaviors and marked delay or disruption of communication and social behavior trajectories that characterize ASD indicate that crucial neuroan...

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