Autism and brain development

Abstract

Genetic studies are refining our understanding of neurodevelopmental mechanisms in autism. Some autism-related mutations appear to disrupt genes regulated by neuronal activity, which are especially important in development of the postnatal nervous system. Gene replacement studies in mice indicate that the developmental window to ameliorate symptoms may be wider than previously anticipated.

Figure 1. The Potential Relationship of Autism Genes to Synaptic Function

Synaptic activity stimulates signaling pathways that ultimately result in the binding in the nucleus of trancsciption factors to specific DNA sequences necessary to activate target genes, Which in turn modify synaptic efficacy. Gene mutations associated with autism affect synaptic proteins such as neuroligins 3 and 4 (NLGN4, NLGN4), neurexin 1 (NRXN1), contactin associated protein-like 2 (CNTNAP2), and SHANK3. These proteins include adhesion molecules of the synapse or cytoplasmic molecules that associate with synaptic receptors. In addition, some genes, such as MECP2 and ARX, which encode proteins that regulate DNA transcription, are associated with autistic features when mutated. Moreover, some of the targets of these activity-dependent transcription factors are mutated in recessive autism. Some autism mutations appear to involve not the coding sequence of genes but rather noncoding sequences that may regulate patterns of gene transcription. For example, PCDH10 and CNTN3 encode proteins that are potentially associated with the synapse yet autism mutations do not alter the coding part of these genes. Together these data suggest that heterogeneous causes of autism may be associated with alterations in activity-dependent synaptic plasticity.