Loss of Tsc1 In Vivo Impairs Hippocampal mGluR-LTD and Increases Excitatory Synaptic Function
Open accessAbstract
The autism spectrum disorder tuberous sclerosis complex (TSC) is caused by mutations in the Tsc1 or Tsc2 genes, whose protein products form a heterodimeric complex that negatively regulates mammalian target of rapamycin-dependent protein translation. Although several forms of synaptic plasticity, including metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), depend on protein translation at the time of induction, it is unknown whether these forms of plasticity require signaling through the Tsc1/2 complex. To examine this possibility, we postnatally deleted Tsc1 in vivo in a subset of hippocampal CA1 neurons using viral delivery of Cre recombinase in mice. We found that hippocampal mGluR-LTD was abolished by loss of Tsc1, whereas a protein synthesis-independent form of NMDA receptor-dependent LTD was preserved. Additionally, AMPA and NMDA receptor-mediated EPSCs and miniature spontaneous EPSC frequency were enhanced in Tsc1 KO neurons. These changes in synaptic function occurred in the absence of alterations in spine density, morphology, or presynaptic release probability. Our findings indicate that signaling through Tsc1/2 is required for the expression of specific forms of hippocampal synaptic plasticity as well as the maintenance of normal excitatory synaptic strength. Furthermore, these data suggest that perturbations of synaptic signaling may contribute to the pathogenesis of TSC.
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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 Bateup et al., 2011
Postnatal deletion of Tsc1 in hippocampal CA1 mouse neurons by viral Cre delivery leads to loss of mGluR-LTD.
“post-natal deletion of Tsc1 in hippocampal CA1 mouse neurons by viral delivery of Cre recombinase led to loss of mGluR–LTD72.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [72]
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- Authors
- Bateup, H. S., Takasaki, K. T., Saulnier, J. L., Denefrio, C. L., & Sabatini, B. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sabatini, B. L.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-06-15
- Volume
- 31
- Issue
- 24
- Pages
- 8862-8869
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3133739
- OpenAlex
- W2005943863
- Cited by
- 204
- References
- 47
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 11 · 2022: 9 · 2021: 14 · 2020: 13 · 2019: 16 · 2018: 16 · 2017: 11 · 2016: 9 · 2015: 25 · 2014: 17 · 2013: 27 · 2012: 19
- FWCI
- 8.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS052707, NS052707)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- TSC1, tuberous sclerosis complex, metabotropic glutamate receptors, long-term depression, synaptic plasticity, mTOR signaling, protein synthesis, excitatory synapses, NMDA receptor, AMPA receptors, miniature EPSCs, CA1 pyramidal neurons, autism spectrum disorder
- MeSH terms
- Animals, Animals, Newborn, Mice, Transgenic, Neurons, Organ Culture Techniques, Serine, Synapses, N-Methylaspartate, Receptors, Glutamate, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Microscopy, Confocal, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Symporters, Long-Term Synaptic Depression, Dendritic Spines, Green Fluorescent Proteins, Mice, CA1 Region, Hippocampal
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