Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities
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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.”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [19]
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.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [2]
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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The human clinical phenotypes of altered CHRNA7 copy number
Gillentine, M. A., & Schaaf, C. P. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.06.012 · Cited by 122 · see citing works
The over‐pruning hypothesis of autism
Thomas, M. S. C., Davis, R., Karmiloff‐Smith, A., Knowland, V. C. P., & Charman, T. (2015) · Developmental Science · doi:10.1111/desc.12303 · Cited by 122 · see citing works
Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients
Yang, Z., Matsumoto, A., Nakayama, K., Jimbo, E. F., Kojima, K., Nagata, K., Iwamoto, S., & Yamagata, T. (2015) · Brain and Development · doi:10.1016/j.braindev.2015.04.006 · Cited by 121 · see citing works
Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c
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Regulation and Roles of Autophagy at Synapses
Nikoletopoulou, V., & Tavernarakis, N. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.03.006 · Cited by 115 · see citing works
Is birth a critical period in the pathogenesis of autism spectrum disorders?
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Statins and the Brain: More than Lipid Lowering Agents?
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Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits
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A Single-Cell Model for Synaptic Transmission and Plasticity in Human iPSC-Derived Neurons
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ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome
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The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders
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NMDA RECEPTOR DYSFUNCTION IN AUTISM SPECTRUM DISORDERS
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PTP1B inhibition suggests a therapeutic strategy for Rett syndrome
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LTD-like molecular pathways in developmental synaptic pruning
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Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid
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- Authors
- Zoghbi, H. Y., & Bear, M. F.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Cold Spring Harbor Perspectives in Biology
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-01-18
- Volume
- 4
- Issue
- 3
- Pages
- a009886-a009886
- ISSN
- 1943-0264 (ISSN-L)
- PMC
- PMC3282414
- 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
- bronze
- doi.org
- 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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