Multiple cannabinoid signaling cascades powerfully suppress recurrent excitation in the hippocampus

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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 CB1Rsensitive 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 αi/o 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.

Original languageEnglish (US)
Article numbere2017590118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number4
StatePublished - Jan 26 2021


  • CB1R
  • Dentate gyrus
  • LTP
  • Metaplasticity
  • Presynaptic

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Multiple cannabinoid signaling cascades powerfully suppress recurrent excitation in the hippocampus'. Together they form a unique fingerprint.

Cite this