Resolving the Synaptic versus Developmental Dichotomy of Autism Risk Genes

Genes that are mutated in Autism Spectrum Disorders (ASD) can be classified broadly as either synaptic or developmental. But what if this is a false distinction? A recent spate of publications has provided evidence for developmental mechanisms that rely on neural activity for proper cortical develop...

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Bibliographic Details
Published in:Trends in neurosciences (Regular ed.) 2020-04, Vol.43 (4), p.227-241
Main Authors: Heavner, Whitney E., Smith, Stephen E.P.
Format: Article
Language:English
Subjects:
autism
chromatin
cortical development
E/I balance
genetics
genomics
neural activity
neuron migration
precision medicine
sensory integration
signal transduction
synapse
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Summary:Genes that are mutated in Autism Spectrum Disorders (ASD) can be classified broadly as either synaptic or developmental. But what if this is a false distinction? A recent spate of publications has provided evidence for developmental mechanisms that rely on neural activity for proper cortical development. Conversely, a growing body of evidence indicates a role for developmental mechanisms, particularly chromatin remodeling, during learning or in response to neural activity. Here, we review these recent publications and propose a model in which genes that confer ASD risk operate in signal transduction networks critical for both cortical development and synaptic homeostasis. Autism Spectrum Disorder (ASD) risk genes are often described as either developmental or synaptic. However, a growing body of evidence shows substantial overlaps and links between these categories, raising the question of how useful the distinction between the two is, in the context of ASD.Developmental processes, such as the radial migration of cortical excitatory neurons and apoptosis of inhibitory neurons, depend on intact excitatory signal transduction.Conversely, genes typically thought of as developmental have important roles in activity-dependent plasticity of excitatory synapses.By homing in on specific biological processes that are disrupted in different ASD models, one may be able to identify biologically relevant subtypes among heterogeneous patient cohorts. We argue that for many patients with ASD, this subgrouping could be more amenable to precision medicine than subgrouping based on behavioral or genetic approaches.
ISSN:0166-2236
1878-108X
DOI:10.1016/j.tins.2020.01.009