Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis

Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL · 2013 · Neuron · Atlas ID BAT2013

What this study shows

Deleting Tsc1 from cultured mouse hippocampal neurons raised phospho-S6 and made the network fire more than twice as much as controls by day 14, in an epilepsy-like bursting pattern; four days of rapamycin brought activity back to control levels. Many gene-expression and synaptic changes in the knockout cultures, such as high Arc and fewer surface AMPA receptors, turned out to be secondary responses to the high activity, not direct effects of mTOR. In hippocampal CA1, Tsc1 loss in single pyramidal neurons weakened the inhibitory synaptic input they received and raised their excitation/inhibition ratio, while their intrinsic excitability was lower, not higher. Forebrain Tsc1 knockout mice had more severe kainate-induced seizures (80% died, while all controls survived), and seven days of rapamycin in vivo restored inhibition and normalised the E/I ratio. Boundary: mouse neurons, cultures and brain slices; Tsc1 deleted in excitatory neurons only; seizure test used a chemical convulsant.

Abstract

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Neural circuits are regulated by activity-dependent feedback systems that tightly control network excitability and which are thought to be crucial for proper brain development. Defects in the ability to establish and maintain network homeostasis may be central to the pathogenesis of neurodevelopmental disorders. Here, we examine the function of the tuberous sclerosis complex (TSC)-mTOR signaling pathway, a common target of mutations associated with epilepsy and autism spectrum disorder, in regulating activity-dependent processes in the mouse hippocampus.

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At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Tsc1 floxed mice: lentiviral Cre in dissociated hippocampal cultures (multi-electrode arrays, microarrays); CaMKIIa-Cre forebrain cKO (kainate seizures); sparse or widespread AAV-Cre in CA1 with slice electrophysiology; rapamycin in vitro and in vivo) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Tsc1 floxed mice: lentiviral Cre in dissociated hippocampal cultures (multi-electrode arrays, microarrays); CaMKIIa-Cre forebrain cKO (kainate seizures); sparse or widespread AAV-Cre in CA1 with slice electrophysiology; rapamycin in vitro and in vivo
Journal	Neuron
Year	2013
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1016/j.neuron.2013.03.017 · PMID 23664616 · Free full text (PMC3690324)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Tsc1 deletion (lentiviral/AAV Cre, CaMKIIa-Cre); rapamycin
Target	TSC1/TSC2 -> mTORC1
Model	Mouse
Effect	Tsc1 loss weakened inhibitory synapses, raised E/I ratio and network excitability; rapamycin reversed it

In the Atlas

Links in the pathway map

Supports TSC1/TSC2 inhibits mTORC1
Supports Rapamycin inhibits mTORC1

Cite this paper

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Bateup, H. S., Johnson, C. A., Denefrio, C. L., Saulnier, J. L., Kornacker, K., & Sabatini, B. L. (2013). Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron. https://doi.org/10.1016/j.neuron.2013.03.017

@article{BAT2013,
  author       = {Bateup, H. S. and Johnson, C. A. and Denefrio, C. L. and Saulnier, J. L. and Kornacker, K. and Sabatini, B. L.},
  title        = {{Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis}},
  journal      = {Neuron},
  year         = {2013},
  doi          = {10.1016/j.neuron.2013.03.017},
  note         = {PMID: 23664616},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record BAT2013) [Data set]. https://mtor-atlas.org/study/BAT2013/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_BAT2013,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record BAT2013},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/BAT2013/},
  doi          = {10.5281/zenodo.22059963}
}

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