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Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin
Open accessAbstract
Retrograde signaling by endocannabinoids (eCBs) mediates a widely expressed form of long-term depression at excitatory and inhibitory synapses (eCB-LTD), involving a reduction in neurotransmitter release. In the hippocampus, eCB-LTD occurs at interneuron (IN)-pyramidal cell (PC) synapses (I-LTD), and its induction requires a presynaptic reduction of cAMP/PKA signaling resulting from minutes of type 1 cannabinoid receptor (CB1R) activation. Although repetitive activity of glutamatergic synapses initiates the eCB mobilization required for I-LTD, it is unclear whether CB1R-containing GABAergic terminals are passive targets of eCBs or whether they actively contribute to induction. Here, we show that the minutes-long induction period for I-LTD may serve as a window to integrate associated spontaneous activity in the same IN receiving the retrograde eCB signal. Indeed, reducing spontaneous IN firing blocked I-LTD, which could be rescued with extra stimulation of inhibitory afferents. Moreover, cell pair recordings showed that a single IN expressed LTD onto a PC only if it was active during eCB signaling. Several methods of disrupting presynaptic Ca(2+) dynamics all blocked I-LTD, strongly suggesting that IN spikes regulate I-LTD by raising Ca(2+) at the nerve terminal. Finally, inhibiting the Ca(2+)-activated phosphatase, calcineurin, fully blocked I-LTD, but blocking another phosphatase did not. Our findings support a model where both CB1R signaling and IN activity shift the balance of kinase and phosphatase activity in the presynaptic terminal to induce I-LTD.
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“In addition, CB1R negatively regulates N- and P/Q-type voltage-gated calcium channels [26] and positively regulates inwardly rectifying K+ channels [26,27], as well as protein serine/threonine phosphatase 2B (calcineurin, PP2B) to change the phosphorylation state of various effector molecules [28,29].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [29]
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Metadata
- Authors
- Heifets, B. D., Chevaleyre, V., & Castillo, P. E.
- Affiliations
- Albert Einstein College of Medicine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-07-22
- Volume
- 105
- Issue
- 29
- Pages
- 10250-10255
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2481322
- OpenAlex
- W2040301525
- Cited by
- 116
- References
- 47
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 2 · 2018: 6 · 2017: 7 · 2016: 8 · 2015: 5 · 2014: 9 · 2013: 11 · 2012: 6
- FWCI
- 7.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- presynaptic plasticity, calcineurin, CB1 receptor, hippocampus, cAMP/PKA signaling, phosphatase activity
- MeSH terms
- Animals, Electric Stimulation, Electrophysiology, Hippocampus, Interneurons, Neuronal Plasticity, Tetrodotoxin, Signal Transduction, Rats, Sprague-Dawley, Pyramidal Cells, Patch-Clamp Techniques, Calcineurin, Calcium Signaling, Long-Term Synaptic Depression, Receptor, Cannabinoid, CB1, Rats, Cannabinoid Receptor Modulators, Endocannabinoids, Calcineurin Inhibitors, In Vitro Techniques
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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