Cited by 797Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

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Zoghbi, H. Y., Bear, M. F.·2012·Cold Spring Harbor Perspectives in Biology

Abstract

The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits.

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  • Neurotransmitter and synaptic pathways were implicated in multiple brain disorders.

    “Not surprisingly, neurotransmitter and synaptic pathways were implicated in multiple brain disorders, supporting decades of studies highlighting the importance of synaptic function in psychiatric disorders19.”
  • Some ASD-associated mutations are limited to a specific gene and cause syndromic neurodevelopmental disorders with highly penetrant autism features, including Fragile X syndrome, tuberous sclerosis complex, Angelman syndrome, Timothy syndrome and Rett syndrome.

    “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.”
  • Increased spine density is observed in frontal, temporal, and parietal lobes in ASD brains, and synaptic structure changes are detected in multiple ASD model mice.

    “Consistently, increased spine density is observed in frontal, temporal, and parietal lobes in ASD brains (Hutsler and Zhang, 2010) and changes in synaptic structure are detected in multiple ASD model mice (Zoghbi and Bear, 2012).”

    From Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits (2014) · cites this paper as Zoghbi and Bear, 2012

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Authors
Zoghbi, H. Y., & Bear, M. F.
Affiliations
Howard Hughes Medical Institute (US)
Venue
Cold Spring Harbor Perspectives in Biology
Published
2012-01-18
Volume
4
Issue
3
Pages
a009886-a009886
ISSN
1943-0264 (ISSN-L)
OpenAlex
W2147140183
Cited by
797
References
268
Citations by year
2026: 40 · 2025: 44 · 2024: 59 · 2023: 50 · 2022: 53 · 2021: 75 · 2020: 87 · 2019: 66 · 2018: 52 · 2017: 61 · 2016: 66 · 2015: 49 · 2014: 46 · 2013: 32 · 2012: 15
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
synaptic dysfunction, neurodevelopmental disorders, autism spectrum disorder, intellectual disability, syndromic autism, genetic causes of autism, neuropsychiatric features, cognitive function, genetic models, model organisms, therapeutic target
MeSH terms
Animals, Child, Child Development Disorders, Pervasive, Disease Models, Animal, Gene Expression Regulation, Humans, Intellectual Disability, Synaptic Transmission, Cell Adhesion Molecules, Neuronal

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