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Synapse-Specific Adaptations to Inactivity in Hippocampal Circuits Achieve Homeostatic Gain Control while Dampening Network Reverberation
Open accessAbstract
Synaptic homeostasis, induced by chronic changes in neuronal activity, is well studied in cultured neurons, but not in more physiological networks where distinct synaptic circuits are preserved. We characterized inactivity-induced adaptations at three sets of excitatory synapses in tetrodotoxin-treated organotypic hippocampal cultures. The adaptation to inactivity was strikingly synapse specific. Hippocampal throughput synapses (dentate-to-CA3 and CA3-to-CA1) were upregulated, conforming to homeostatic gain control in order to avoid extreme limits of neuronal firing. However, chronic inactivity decreased mEPSC frequency at CA3-to-CA3 synapses, which were isolated pharmacologically or surgically. This downregulation of recurrent synapses was opposite to that expected for conventional homeostasis, in apparent conflict with typical gain control. However, such changes contributed to an inactivity-induced shortening of reverberatory bursts generated by feedback excitation among CA3 pyramids, safeguarding the network from possible runaway excitation. Thus, synapse-specific adaptations of synaptic weight not only contributed to homeostatic gain control, but also dampened epileptogenic network activity.
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“Interestingly, not all excitatory neurons in cortical networks express synaptic scaling.In hippocampal networks CA1 neurons scale synapses up in response to activity blockade, whereas CA3 neurons do not (Kim and Tsien 2008).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Kim and Tsien 2008
In the citing paper
“Interestingly, not all excitatory neurons in cortical networks express synaptic scaling.In hippocampal networks CA1 neurons scale synapses up in response to activity blockade, whereas CA3 neurons do not (Kim and Tsien 2008).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Kim and Tsien 2008
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“This sets the interpretation of our data apart from any developmental influence; this is of relevance because responses to inactivity may vary widely depending on the maturity of the neural network (Burrone et al., 2002; Hartman et al., 2006; Karmarkar and Buonomano, 2006; Kirov et al., 2004).”
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“Even neural networks have mechanisms for synapse-specific adaptation to keep neuronal firing within the range of useful information flow by avoiding runaway exci - tation and extreme neuronal activity (Kim and Tsien 2008).”
Unreliable homeostatic action potential broadening in cultured dissociated neuronsPreprint
Ritzau‐Jost, A., Rajayer, S. R., Nerlich, J., Maciąg, F., John, A., Russier, M., Sabater, V. G., Steiger, L. J., Coq, J., Eilers, J., et al. (2025) · eLife · doi:10.1101/2025.05.09.653135
“2E [14.1–17.4] pA in control and TTX-treated cells, 16 and 11 cells, respectively, P = 0.042), in accord with known homeostatic synaptic adaptations to inactivity 24–27 .”
InfluentialVergara, P., Pino, G., Vera, J. R., Arancibia, F., & Sanhueza, M. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.821088 · Cited by 1
Vergara, P., Pino, G., Vera, J., & Sanhueza, M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.09.467941
“Long-lasting action potential inhibition by tetrodotoxin (TTX) in the hippocampus in vivo or in slice cultures induces complex cell-type-dependent synaptic adaptations (Echegoyen et al., 2007)(Kim and Tsien, 2008).”
BackgroundDubes, S., Soula, A., Benquet, S., Tessier, B., Poujol, C., Favereaux, A., Thoumine, O. R., & Letellier, M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.30.442089
“Moreover, integrated and/or mature synaptic circuits appear less prone to undergo multiplicative scaling in comparison to immature circuits or in vitro models (Cingolani and Goda, 2008; Echegoyen et al., 2007; Goel and Lee, 2007; Hobbiss et al., 2018; Kim and Tsien, 2008; Lee and Kirkwood, 2019).”
BackgroundZbili, M., Rama, S., Benítez, M., Fronzaroli-Molinieres, L., Bialowas, A., Boumedine-Guignon, N., Garrido, J., & Debanne, D. (2021) · bioRxiv · doi:10.1101/2021.04.22.440937
“Increase in spontaneous mEPSCs but not evoked mEPSCs in AD neurons To test whether the increase in synaptic strength in AD cultures goes with an increase in postsynaptic receptors density we recorded spontaneous miniatures EPSCs (mEPSCs) in CA3 neurons of control and AD organotypic cultures while blocking spiking with…”
BackgroundDubes, S. (2019) · theses.fr (ABES) · doi:10.70675/275d3182za2b9z4513z9941z62d044306e33
“…du glutamate en réponse au traitement chronique avec la TTX. Aux synapses formées entre les neurones pyramidaux CA3 et CA1, c’est en revanche l’amplitude des CPSEs qui est augmentée de manière multiplicative soulignant une réponse homéostatique de type synaptic scaling (Kim and Tsien, 2008).”
BackgroundThe reversibility and limits of homeostatic synaptic plasticity
Yeates, C. J. (2018) · doi:10.17077/etd.1t8ov7dk
“9 plasticity in networks (Kim and Tsien, 2008), as well as homeostatic control of presynaptic release in a similar manner to what is seen in homeostatic plasticity in Drosophila (Henry et al.”
ResultLee, K. (2015) · doi:10.20381/ruor-4781
“This was perhaps best illustrated by a series of experiments studying HSP in TTX-treated organotypic hippocampal slice cultures (Kim and Tsien, 2008; Deeg, 2009).”
BackgroundInfluentialNassrallah, W. B. (2015) · uO Research (University of Ottawa) · doi:10.20381/ruor-4032
“In this manner, the weakening of these reverberant synapses was said to stabilise the network by reducing epileptic activity (Kim & Tsien, 2008).”
Background
Metadata
- Authors
- Kim, J., & Tsien, R. W.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Tsien, Richard W.
- ORCID
- Tsien, Richard W.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 58
- Issue
- 6
- Pages
- 925-937
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2561251
- OpenAlex
- W2001651016
- Cited by
- 124
- References
- 0
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 7 · 2023: 2 · 2022: 5 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 4 · 2017: 7 · 2016: 4 · 2015: 6 · 2014: 9 · 2013: 20 · 2012: 8
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R37MH071739)
- National Institute of General Medical Sciences (R01GM058234)
- National Institute of Neurological Disorders and Stroke (R01NS024067)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- synaptic homeostasis, hippocampus, excitatory synapses, CA3 pyramidal cells, epileptogenesis, organotypic hippocampal slice cultures, tetrodotoxin
- MeSH terms
- Adaptation, Physiological, Animals, Hippocampus, Homeostasis, Nerve Net, Neural Inhibition, Neuronal Plasticity, Synapses, Rats, Sprague-Dawley, Excitatory Postsynaptic Potentials, Rats
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