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Multiple cannabinoid signaling cascades powerfully suppress recurrent excitation in the hippocampus.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jan 26; Vol. 118 (4). - Publication Year :
- 2021
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Abstract
- Recurrent excitatory neural networks are unstable. In the hippocampus, excitatory mossy cells (MCs) receive strong excitatory inputs from dentate granule cells (GCs) and project back onto the proximal dendrites of GCs. By targeting the ipsi- and contralateral dentate gyrus (DG) along the dorsoventral axis of the hippocampus, MCs form an extensive recurrent excitatory circuit (GC-MC-GC) whose dysregulation can promote epilepsy. We recently reported that a physiologically relevant pattern of MC activity induces a robust form of presynaptic long-term potentiation (LTP) of MC-GC transmission which enhances GC output. Left unchecked, this LTP may interfere with DG-dependent learning, like pattern separation-which relies on sparse GC firing-and may even facilitate epileptic activity. Intriguingly, MC axons display uniquely high expression levels of type-1 cannabinoid receptors (CB1Rs), but their role at MC-GC synapses is poorly understood. Using rodent hippocampal slices, we report that constitutively active CB1Rs, presumably via βγ subunits, selectively inhibited MC inputs onto GCs but not MC inputs onto inhibitory interneurons or CB1R-sensitive inhibitory inputs onto GCs. Tonic CB1R activity also inhibited LTP and GC output. Furthermore, brief endocannabinoid release from GCs dampened MC-GC LTP in two mechanistically distinct ways: during induction via βγ signaling and before induction via α <subscript>i/o</subscript> signaling in a form of presynaptic metaplasticity. Lastly, a single in vivo exposure to exogenous cannabinoids was sufficient to induce this presynaptic metaplasticity. By dampening excitatory transmission and plasticity, tonic and phasic CB1R activity at MC axon terminals may preserve the sparse nature of the DG and protect against runaway excitation.<br />Competing Interests: The authors declare no competing interest.
- Subjects :
- Action Potentials drug effects
Action Potentials physiology
Animals
Animals, Newborn
Cannabinoid Receptor Agonists pharmacology
Cannabinoid Receptor Antagonists pharmacology
Cannabinoids pharmacology
Dentate Gyrus cytology
Dentate Gyrus drug effects
Excitatory Postsynaptic Potentials drug effects
Gene Expression
Hippocampus cytology
Hippocampus drug effects
Interneurons cytology
Interneurons drug effects
Interneurons metabolism
Long-Term Potentiation drug effects
Mice
Piperidines pharmacology
Pyrazoles pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1 metabolism
Synapses drug effects
Synapses physiology
Synaptic Transmission
Dentate Gyrus metabolism
Excitatory Postsynaptic Potentials physiology
Hippocampus metabolism
Long-Term Potentiation physiology
Receptor, Cannabinoid, CB1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 33468648
- Full Text :
- https://doi.org/10.1073/pnas.2017590118