Activity-dependent neuronal signalling and autism spectrum disorder

About 1 in 100 children display signs and symptoms that lead to a diagnosis of autism spectrum disorder (ASD)1. This debilitating developmental disorder is characterized by impairments in social interaction and communication, and by restricted, repetitive and stereotyped behaviour and interests. In addition, individuals with ASD often have a seizure disorder and intellectual disability2. Most of these features of ASD manifest in the first few years of life, at the time of brain development when sensory experience is modifying excitatory synapse maturation and elimination, and promoting the development of inhibitory synapses3. This has led to the hypothesis that ASD may be due to a disruption of the normal process of experience-dependent synaptic development, resulting in an imbalance between excitation and inhibition in the developing brain. Research has shown unequivocally that ASD is largely a genetic disorder4. Advances in human genetics and next-generation sequencing have identified a stunning number of newly arising mutations that are linked to ASD. In some cases, the mutations are limited to a specific gene and result in syndromic neurodevelopmental disorders with highly penetrant features of autism. These include Fragile X syndrome, tuberous sclerosis complex, Angelman syndrome, Timothy syndrome and Rett syndrome2. In addition, an impressive array of human genetic studies, including studies of families with several children with ASD and more recent exome sequencing of trios of individuals (mother, father and child with ASD), has surprisingly shown that ASD is often due to newly arising gene copy number variants (CNVs) — such as a deletion or duplication of a region of a chromosome — or a rare mutation that arises in the germ cell, particularly in sperm of older fathers5–10. In cases with CNVs, ASD is hypothesized to be a result of the increased or decreased expression of one, or several, genes that lie within the region of the genome in which the CNV mutation resides. A future challenge is to make biological sense of the large number, and diversity, of genes that are associated with ASD. Identifying convergent molecular pathways in which multiple candidate genes are involved may be an effective way to advance our understanding of the underlying molecular basis for ASD, as well as a way to develop treatments for a broad range of forms of this disorder. Recent studies suggest that a convergent molecular pathway dysregulated in ASD is the signalling network that controls synapse development and function. An interesting feature of this signalling network is that it is composed of many proteins for which expression or function is regulated by neuronal activity, suggesting that one cause of ASD may be the dysregulation of neuronal activity-dependent synapse development and function. A cardinal feature of human brain development is that sensory, cognitive and emotional experiences shape synapse and neural-circuit development. Neuronal activity triggers local changes at the synapse, altering the composition, shape and strength of the synapse. Synaptic stimulation both induces specific changes in messenger RNA translation near synapses and sends signals to the nucleus to induce gene transcription programs that control synaptic maturation and function. These neuronal activity-dependent pathways are crucial to learning and memory and for adaptive behavioural responses11–13. In this Review, we explore the hypothesis that the dysregulation of activity-dependent signalling networks that control synapse development and function may be an important component of the molecular basis of ASD. For instance, ASD may arise from dysregulation of activity-dependent signalling pathways locally at a synapse, including changes in the post-translational modifications of synaptic proteins and the local translation of mRNAs at synapses, as well as from the dysregulation of activity-dependent gene transcription. Alternative explanations for the molecular and cellular basis of ASD must also be considered, including the possibility that it is a result of dysregulation of synaptic function in general, impairment of neurotransmission (which secondarily may alter activity-dependent signalling) and defects in earlier steps in nervous-system development. To begin to evaluate these hypotheses, we review studies of the molecular function of the most studied genes that are associated with ASD, including those for syndromic disorders with penetrant autism spectrum features and rare mutations associated with ASD. The current weight of evidence does not conclusively demonstrate that dysregulation of activity-dependent neuronal signalling is the singular cause of ASD. Indeed, impairment of multiple, different molecular pathways that are not mutually exclusive, probably contributes to the development of various subsets, or aspects, of ASD. However, as we review here, there is emerging evidence that genes and proteins associated with ASD are both regulated by and control activity-dependent pathways that modulate synaptic function. Many of the mutations associated with ASD lead to alterations in excitatory or inhibitory neurotransmission that disrupt activity-dependent signalling and disrupt activity-dependent synapse development, maturation and refinement. In addition, neuronal activity clearly regulates the function, localization and expression of many of the proteins that are associated with ASD. Taken together, these findings are beginning to provide compelling evidence that disruption of activity-dependent molecular programs that control synaptic function significantly contributes to the molecular basis of ASD.