Scientific Understanding of Consciousness
Autism Spectrum Disorders
Science 14 September 2012: Vol. 337 no. 6100 pp. 1301-1303
The Emerging Biology of Autism Spectrum Disorders
Matthew W. State, Nenad Šestan
1Child Study Center and Departments of Psychiatry
2Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Autism spectrum disorders (ASD) are a genetically and phenotypically heterogeneous group of syndromes defined by fundamental impairments in social reciprocity and language development accompanied by highly restrictive interests and/or repetitive behaviors. Recent advances in genetics, genomics, developmental neurobiology, systems biology, monogenic neurodevelopment syndromes, and induced pluripotent stem cells (iPSC) are now offering remarkable insights into their etiologies and converging to provide a clear and immediate path forward from the bench to the bedside.
Multiple studies have confirmed that rare and de novo point mutations and submicroscopic variations in chromosomal structure contribute to a considerable number of cases and have identified a growing number of specific genomic intervals and genes conferring risks. These advances provide a critical foundation for the development of a more refined understanding of the biological underpinnings of ASD. The earliest findings in the genetics of idiopathic (nonsyndromic) autism highlighted the role of synaptic adhesion molecules and postsynaptic density proteins. A set of newly discovered ASD proteins expands this view, highlighting a role for chromatin modifiers (CHD8), and DNA binding proteins (POGZ), ion channels (SCN2A), microtubule-associated proteins (KATNAL2), neurotransmitter receptors (GRIN2B), and phosphorylation-regulated tyrosine kinases (DYRK1A)
The recent emergence of comprehensive maps of spatiotemporal gene expression in the human brain, the ability to construct similar maps of gene-regulatory interactions and chromatin states, and the availability of a growing list of definitive ASD point mutations sets the stage for a powerful developmentally informed approach to studying ASD biology.
The available published data on ASD gene expression in the developing human brain already points to some intriguing etiological hypotheses and plausible explanations for the observation that a single genetic risk variant can lead to highly divergent phenotypes, including autism and schizophrenia.
Many of the ASD genes exhibit distinctive spatiotemporal expression patterns in the developing brain, including dramatic increases in the cerebral cortex during mid-gestation, a developmental period crucial for the formation of early neural circuits.
Early cortical neuronal differentiation and synapse formation are present in the regions that give rise to circuits underlying executive control, social affective processing, and language—all functions that are altered in ASD.
These early regional differences in the timing of synaptogenesis may help explain why the ontogenetically older circuits involved in these processes are particularly vulnerable in ASD, whereas other cortical processes, such as vision, are less affected.
Several lines of evidence indicate that cortical areas and their circuits mature at different rates during postnatal development. Higher-order association cortices, including prefrontal and temporal cortices, do not fully mature until late adolescence and early adulthood, and some of their maturational trajectories are altered in ASD and schizophrenia. Their extended period of maturation may increase the sensitivity of the ontogenetically older frontal and temporal circuits involved in executive control, social affective processing, and language, to both ongoing alterations in the molecular landscape, and interceding environmental insults. In short, the identical genetic risk could lead to variable phenotypes via early developmental and ongoing functional alterations in temporally defined molecular interactions in neural circuits that show both early vulnerability and an extended period of maturational sensitivity.
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