Mutations causing syndromic autism define an axis of synaptic pathophysiology
Open accessAbstract
Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2(+/-) and Fmr1(-/y) mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.
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LTD is attenuated in Tsc2+/- mice and in the Tsc2ΔRG loss-of-function mutant.
“Furthermore, LTD is attenuated, both in Tsc2+/- (Auerbach et al., 2011; Bateup et al., 2011), and in a loss of function mutant, Tsc2ΔRG, that weakens translational braking (Chevere-Torres et al., 2012).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Auerbach et al., 2011
Genes involved in ASD seem to converge on common pathways altering synaptic homeostasis.
“Genes involved in ASD seem to converge on common pathways altering synaptic homeostasis.”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [16]
A reduction in the number of dendrites was observed in Rett and tuberous sclerosis syndromes, whereas a high density of dendrites was reported in fragile X syndrome.
“For example, a reduction in the number of dendrites was observed in Rett and tuberous sclerosis syndromes, whereas a high density of dendrites was reported in fragile X syndrome 16 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [16]
Inhibition of mTOR in Tsc2+/- mice restored mGluR-LTD and normalized protein synthesis rates to wild-type levels.
“Inhibition of mTOR in Tsc2+/− mice restored mGluR–LTD and normalized protein synthesis rates to that of wild-type mice rates”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [71]
Tsc2+/- mice have decreased translation of Arc mRNA compared to wild-type mice.
“Compared with wild-type mice, Tsc2+/− mice have decreased translation of Arc mRNA71.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [71]
Tsc2+/- mice have deficient mGluR-LTD in the hippocampus but no defect in basal synaptic transmission.
“Mice with a heterozygous loss of function mutation in Tsc2 (Tsc2+/−) have deficient mGluR–LTD in the hippocampus, but no defect in basal synaptic transmission.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [71]
In fear conditioning, Tsc2+/- mice have a defect in distinguishing familiar and new contexts, which can be corrected by augmentation of mGluR5 signalling.
“In a fear conditioning behavioural model, Tsc2+/− mice have a defect in distinguishing familiar and new contexts, a defect that can also be corrected by augmentation of mGluR5 signalling71.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [71]
Inhibition of mGluR5 in Fmr1 knockout mice corrects excessive protein synthesis and mGluR5-dependent LTD; augmentation of mGluR5 signalling restores protein synthesis and mGluR-dependent LTD in Tsc2+/- mice.
“Whereas inhibition of mGluR5 in Fmr1 knockout mice corrects excessive protein synthesis and mGluR5-dependent LTD, augmentation of mGluR5 signalling by a positive allosteric modulator restored protein synthesis and mGluR-dependent LTD in Tsc2+/− mice71.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [71]
Excessive mTOR activity leads to decreased protein synthesis and LTD deficiency in Tsc2+/- mice.
“suggesting that excessive mTOR activity leads to decreased protein synthesis and LTD deficiency in Tsc2+/− mice71.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [71]
Reference 71 shows that loss of function of TSC1-TSC2 or FMRP disrupts activity-regulated mRNA translation and synaptic plasticity in opposite directions.
“This paper shows that loss of function of either TSC1–TSC2 or FMRP disrupt activity-regulated mRNA translation and synaptic plasticity in opposite directions.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [71]
Mouse models of Rett syndrome, Angelman syndrome, tuberous sclerosis complex, Fragile X syndrome, and rare SHANK mutations have provided strong evidence that interventions of a genetic or pharmacological nature can improve ASD phenotypes.
“Several mouse models of ASD, including those of Rett syndrome96,97, Angelman syndrome98, tuberous sclerosis complex71, and Fragile X23 syndrome, and mouse models of rare mutations in SHANK proteins49, have provided convincing evidence that ASD phenotypes can be improved by genetic or pharmacological interventions”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [71]
FMRP may act as one component of a central regulator of synaptic plasticity, among others such as TSC2.
“FMRP may act as one component of a central regulator of synaptic plasticity, among others such as TSC2 (Darnell et al., 2011; Auerbach et al., 2011).”
From De Novo Gene Disruptions in Children on the Autistic Spectrum (2012) · cites this paper as Auerbach et al., 2011
Crossing Tsc2 heterozygous mice with Fmr1 knockout mice rescued the fragile X syndrome phenotype with normalization of neuronal protein synthesis and electrophysiological responses.
“In another study, mice heterozygous for the tuberous sclerosis complex 2 (Tsc2 +/-mice), a GTPase-activating protein known to inhibit the kinase mTOR (Figure 2), were crossed with the Fmr1 KO mice.Also in this case, the FXS phenotype was rescued with normalization of neuronal protein synthesis and electrophysiological responses (92).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [92]
Because both mouse models have upregulated mTOR pathway activity, normal synaptic plasticity and cognition may occur within an optimal range of mGluR-mediated protein synthesis, such that deviations in either direction can lead to shared behavioral impairments.
“Because both mouse models have upregulated mTOR pathway activity, the authors propose that normal synaptic plasticity and cognition occur within an optimal range of mGluRmediated protein synthesis, such that deviations in either direction can lead to shared behavioral impairments.”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [92]
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- Authors
- Auerbach, B. D., Osterweil, E. K., & Bear, M. F.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bear, Mark F.
- Venue
- Nature
- Published
- 2011-11-23
- Volume
- 480
- Issue
- 7375
- Pages
- 63-68
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3228874
- OpenAlex
- W2157742595
- Cited by
- 592
- References
- 46
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 25 · 2023: 20 · 2022: 32 · 2021: 44 · 2020: 32 · 2019: 33 · 2018: 27 · 2017: 51 · 2016: 57 · 2015: 57 · 2014: 57 · 2013: 72 · 2012: 67
- FWCI
- 38.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- PMC
- Funders
- U.S. Department of Defense (W81XWH-11-1-, W81XWH)
- Howard Hughes Medical Institute
- Simons Foundation
- National Institute of Mental Health (T32MH074249, T32MH082718)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD046943)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- tuberous sclerosis complex, fragile X syndrome, autism spectrum disorder, intellectual disability, synaptic plasticity, synaptic dysfunction, neuronal protein synthesis, metabotropic glutamate receptor 5, TSC2, FMR1 gene, hippocampus, cognitive impairment
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, Animals, Autistic Disorder, Disease Models, Animal, Female, Gene Expression Regulation, Hippocampus, Male, Mice, Inbred C57BL, Mutation, Syndrome, Receptors, Metabotropic Glutamate, Tumor Suppressor Proteins, Mice, Fragile X Messenger Ribonucleoprotein 1, Electrical Synapses, TOR Serine-Threonine Kinases, Receptor, Metabotropic Glutamate 5
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