From the genetic architecture to synaptic plasticity in autism spectrum disorder

Key Points

  • Twin and familial studies reveal that autism spectrum disorder (ASD) traits are highly heritable.

  • The genetic landscape of ASD is made of common and rare variants and can be different from one individual to another.

  • Most of the ASD-risk genes are involved in chromatin remodelling, regulation of protein synthesis and degradation, or synaptic plasticity.

  • In cellular and animal models, mutations in the ASD-risk genes lead to a distortion of typical neuronal connectivity by decreasing or increasing synapse strength or number.

  • Compensatory mechanisms, such as genetic buffering and synaptic homeostasis, could modulate the severity of these mutations.

Abstract

Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.

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Figure 1: The genetic risk of ASD.
Figure 2: The interplay between rare mutations and genetic background.
Figure 3: Chromatin remodelling and transcription factors associated with ASD.
Figure 4: Main synaptic functions associated with ASD.
Figure 5: Possible effects of genetic mutations on neuronal connectivity in ASD.

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Acknowledgements

The author thanks Sophie Calderari, Guillaume Dumas, Elodie Ey, Eva Loth, Thomas Rolland and Roberto Toro for their discussions and reading of the manuscript. This work was funded by the Institut Pasteur, Fondation Bettencourt Schueller, Centre National de la Recherche Scientifique, University Paris Diderot, Agence Nationale de la Recherche (SynDivAutism), the Conny-Maeva Charitable Foundation, Fondation Cognacq-Jay, the Orange Foundation and Fondation FondaMental. The research leading to these results has also received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in-kind contribution.

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Examples of genes associated with ASD and their main clinical phenotypes. (PDF 371 kb)

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Proteins associated with ASD and their binding partners. (PDF 211 kb)

Glossary

Dysmorphic features

Differences in body structure compared with that in the general population. Dysmorphic features can be isolated or multiple and vary from mild anomalies, such as minor malformations of the fingers, to more severe differences, such as microcephaly.

Synaptic homeostasis

Crosstalk between the presynaptic and the postsynaptic sides of the synapse that allows the tight regulation of synaptic strength and thus maintains excitability within a narrow range. It stabilizes neuronal circuits and ensures the fidelity of communication within the neuronal network despite sensory and/or growth-dependent changes.

Single-nucleotide variants

(SNVs). DNA-sequence variations occurring within a population. SNV is the general term for all such variations. Single-nucleotide polymorphism is usually used for SNVs occurring in > 1% of the population.

Copy-number variants

(CNVs). Variations in the number of copies of one segment of DNA. CNVs include deletions and duplications.

Psychological and cognitive tests

Various self- and parent-reports designed to reliably quantify autistic traits in the general population and in clinical cases. Examples of theses scales are the social responsiveness scale and the autism spectrum quotient.

Heritability

The proportion of the phenotypic variance that is due to genetic factors. In the narrow sense, heritability includes only the additive genetic component. However, in the broad sense, heritability includes both the additive and the dominance genetic components.

Dominance components

Part of the genetic contribution to a phenotype, the other part of which is the additive component. Some genes have an additive effect on the quantitative trait, whereas other genes may exhibit a dominant gene action, which will mask the contribution of the recessive alleles at the locus.

Quantitative molecular genetics

A branch of population genetics that assesses the heritability of continuously distributed phenotypes based on their molecular genetic signatures. For example, the Genome-Wide Complex Trait Analysis (GCTA) software estimates genomic relationships between pairs of conventionally unrelated individuals using single-nucleotide polymorphism (SNP) data.

Gene dosage

The number of copies of a gene that are present in a cell. An abnormal gene dosage (by gene deletion or duplication) can result in abnormal levels of gene product formation. Gene dosage compensation to adjust the normal level of gene product can occur at different levels (transcription, translation and degradation).

Genetic buffer

The process by which an individual's genetic background can moderate or counteract the phenotypic effect of deleterious mutations.

Chromatin remodelling

The dynamic modification of chromatin architecture to allow or deny access of condensed genomic DNA to the regulatory transcription machinery proteins, thereby controlling gene expression.

X inactivation

A process by which one of the two copies of the X chromosome present in female mammals is inactivated.

Synaptic scaling

A form of synaptic plasticity that adjusts the strength of a neuron's excitatory synapses up or down to stabilize firing.

Metaplasticity

The plasticity of synaptic plasticity (that is, the prior history of activity of a synapse determines its current plasticity).

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Bourgeron, T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci 16, 551–563 (2015). https://doi.org/10.1038/nrn3992

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