Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection
Δ9-tetrahydrocannabinol (THC), the chief psychoactive ingredient of cannabis, acts in the brain primarily via cannabinoid CB1 receptors. These receptors are implicated in several forms of synaptic plasticity – depolarization-induced suppression of excitation (DSE), metabotropic suppression of excita...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000313 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1825199566337605632 |
|---|---|
| author | Michaela Dvorakova Ken Mackie Alex Straiker |
| author_facet | Michaela Dvorakova Ken Mackie Alex Straiker |
| author_sort | Michaela Dvorakova |
| collection | DOAJ |
| description | Δ9-tetrahydrocannabinol (THC), the chief psychoactive ingredient of cannabis, acts in the brain primarily via cannabinoid CB1 receptors. These receptors are implicated in several forms of synaptic plasticity – depolarization-induced suppression of excitation (DSE), metabotropic suppression of excitation (MSE), long term depression (LTD) and activation-dependent desensitization. Cultured autaptic hippocampal neurons express all of these, illustrating the rich functional and temporal heterogeneity of CB1 at a single set of synapses. Here we report that coincident activation of muscarinic acetylcholine receptors and elicitation of DSE in autaptic hippocampal neurons results in a substantial (∼40 %) and temporally precise inhibition of excitatory transmission lasting ∼10 minutes. Its induction is blocked by CB1 and muscarinic M3/M5 receptor antagonists and is absent in CB1 receptor knockout neurons. Notably, once it is established, inhibition is reversed by a CB1, but not a muscarinic, antagonist, suggesting that the inhibition occurs via persistent activation of CB1 receptors. We refer to this inhibition as muscarinic cannabinoid suppression of excitation (MCSE). MCSE can be mimicked by coapplication of muscarinic and cannabinoid agonists and requires Ca2+-release from internal stores. As such, MCSE represents a novel and targeted form of coincidence detection – important for many modes of learning and memory -- between cannabinoid and muscarinic signaling systems that elicits a medium-duration depression of synaptic signaling. Given the known roles of muscarinic and cannabinoid receptors in the hippocampus, MCSE may be important in the modulation of hippocampal signaling at the site of septal inputs, with potential implications for learning and memory, epilepsy and addiction. |
| format | Article |
| id | doaj-art-4edf4e86b66e48fcb80458c6203d0d71 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-4edf4e86b66e48fcb80458c6203d0d712025-02-08T04:59:50ZengElsevierPharmacological Research1096-11862025-02-01212107606Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detectionMichaela Dvorakova0Ken Mackie1Alex Straiker2Gill Institute for Neuroscience, United States; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United StatesGill Institute for Neuroscience, United States; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United StatesGill Institute for Neuroscience, United States; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States; Correspondence to: Gill Center for Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States.Δ9-tetrahydrocannabinol (THC), the chief psychoactive ingredient of cannabis, acts in the brain primarily via cannabinoid CB1 receptors. These receptors are implicated in several forms of synaptic plasticity – depolarization-induced suppression of excitation (DSE), metabotropic suppression of excitation (MSE), long term depression (LTD) and activation-dependent desensitization. Cultured autaptic hippocampal neurons express all of these, illustrating the rich functional and temporal heterogeneity of CB1 at a single set of synapses. Here we report that coincident activation of muscarinic acetylcholine receptors and elicitation of DSE in autaptic hippocampal neurons results in a substantial (∼40 %) and temporally precise inhibition of excitatory transmission lasting ∼10 minutes. Its induction is blocked by CB1 and muscarinic M3/M5 receptor antagonists and is absent in CB1 receptor knockout neurons. Notably, once it is established, inhibition is reversed by a CB1, but not a muscarinic, antagonist, suggesting that the inhibition occurs via persistent activation of CB1 receptors. We refer to this inhibition as muscarinic cannabinoid suppression of excitation (MCSE). MCSE can be mimicked by coapplication of muscarinic and cannabinoid agonists and requires Ca2+-release from internal stores. As such, MCSE represents a novel and targeted form of coincidence detection – important for many modes of learning and memory -- between cannabinoid and muscarinic signaling systems that elicits a medium-duration depression of synaptic signaling. Given the known roles of muscarinic and cannabinoid receptors in the hippocampus, MCSE may be important in the modulation of hippocampal signaling at the site of septal inputs, with potential implications for learning and memory, epilepsy and addiction.http://www.sciencedirect.com/science/article/pii/S1043661825000313CB1 receptorM3/M5 muscarinic receptorsSynaptic plasticityAutaptic hippocampal neurons |
| spellingShingle | Michaela Dvorakova Ken Mackie Alex Straiker Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection Pharmacological Research CB1 receptor M3/M5 muscarinic receptors Synaptic plasticity Autaptic hippocampal neurons |
| title | Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection |
| title_full | Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection |
| title_fullStr | Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection |
| title_full_unstemmed | Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection |
| title_short | Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection |
| title_sort | muscarinic cannabinoid suppression of excitation a novel form of coincidence detection |
| topic | CB1 receptor M3/M5 muscarinic receptors Synaptic plasticity Autaptic hippocampal neurons |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000313 |
| work_keys_str_mv | AT michaeladvorakova muscariniccannabinoidsuppressionofexcitationanovelformofcoincidencedetection AT kenmackie muscariniccannabinoidsuppressionofexcitationanovelformofcoincidencedetection AT alexstraiker muscariniccannabinoidsuppressionofexcitationanovelformofcoincidencedetection |