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Dendritic structural plasticity and neuropsychiatric disease

Key Points

  • The development of dendritic branches and spines, which host the excitatory postsynaptic machinery, is atypical in neuropsychiatric disorders.

  • Genetic risk factors for neuropsychiatric disease converge on genes that encode proteins present in excitatory postsynaptic termini with known roles in dendritic structural plasticity.

  • Risk variants in genes regulating structural plasticity may explain the atypical dendrite and spine development observed in individuals with neuropsychiatric disorders.

  • Drug discovery efforts targeting the genetic risk factors affecting the structural plasticity of dendritic spines have been successful in improving patient outcomes. Genetics may facilitate the prioritization, or elucidation, of drug targets within neuropsychiatric disorders.

  • Stem cell models can be used to model the structural deficits in individuals with neuropsychiatric disease, offering an avenue for screening personalized treatments.

Abstract

The structure of neuronal circuits that subserve cognitive functions in the brain is shaped and refined throughout development and into adulthood. Evidence from human and animal studies suggests that the cellular and synaptic substrates of these circuits are atypical in neuropsychiatric disorders, indicating that altered structural plasticity may be an important part of the disease biology. Advances in genetics have redefined our understanding of neuropsychiatric disorders and have revealed a spectrum of risk factors that impact pathways known to influence structural plasticity. In this Review, we discuss the importance of recent genetic findings on the different mechanisms of structural plasticity and propose that these converge on shared pathways that can be targeted with novel therapeutics.

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Figure 1: Spine and dendrite development in health and disease.
Figure 2: Mechanisms of structural plasticity.
Figure 3: Neuropsychiatric risk factors and biological pathways regulating structural plasticity.
Figure 4: Pharmacological targets and associated structural pathways within the dendritic spine.

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Acknowledgements

The authors thank M. D. Martin-de-Saavedra and K. Myczek for lively discussions and critical input on preparing the manuscript.

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M.P.F., E.P. and P.P. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Peter Penzes.

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Supplementary Table S1

Neuropsychiatric risk loci with a reported effect on structural plasticity (PDF 555 kb)

Glossary

Dendritic spines

Micrometre protrusions on dendritic branches of neurons that host the majority of excitatory synapses in the brain.

Genetic risk factors

DNA sequence variants that are associated with increased disease susceptibility.

Synaptic input field

The total number and spatial arrangement of a neurons postsynaptic receptors. This postsynaptic field is determined by the architecture of the dendritic tree and the number and size of receptor domains contained within dendritic spines.

Postsynaptic density

(PSD). A specialization on excitatory dendritic spines, originally identified by electron microscopy, which contains glutamate receptors and many associated scaffolding and trafficking proteins that are crucial for excitatory synaptic transmission.

Long-term potentiation

(LTP). Long-lasting increase in synaptic strength between neurons, usually resulting from synchronous or temporally coordinated presynaptic and postsynaptic activity.

Long-term depression

(LTD). Long-lasting weakening of synaptic strength between neurons, often resulting from asynchronous presynaptic and postsynaptic activity.

Cell reprogramming technologies

Techniques in biotechnology used to convert one cell type into another using defined biological factors; for example, transcription factors can be introduced into adult somatic cells to reprogramme them into induced pluripotent stem cells or induced neurons.

Common variants

Alterations in a DNA sequence, often with small effect on disease risk, which are present in large proportion of the general population (> 1%). These are typically single-nucleotide polymorphisms that are identified in genome-wide association study (GWAS).

Rare variants

Mutations in a DNA sequence, often with a large effect on disease risk, which occur only in a small fraction of the general population (< 1%). These types of variants are usually identified in family, exome sequencing or copy number variant (CNV) studies.

Genome-wide association studies

(GWAS). Genetic studies designed to identify variants in the genome that associate with a disease or trait. Large-scale GWAS have been especially successful in identifying many common risk variants in schizophrenia and bipolar disorder.

Exome sequencing

Genomic sequencing technique used to sequence all of the protein-coding regions (exons) of the genome.

Enrichment analyses

Bioinformatic technique used to identify over-represented gene sets or biological processes from large omic data sets. This method is typically used to understand the concerted function of hundreds of genes and/or proteins from genomic and proteomic data.

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Forrest, M., Parnell, E. & Penzes, P. Dendritic structural plasticity and neuropsychiatric disease. Nat Rev Neurosci 19, 215–234 (2018). https://doi.org/10.1038/nrn.2018.16

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