Cannabinoid Control of Learning and Memory through HCN Channels

Mattia Maroso, Gergely G. Szabo, Hannah K. Kim, Allyson Alexander, Anh D. Bui, Sang Hun Lee, Beat Lutz, Ivan Soltesz

Research output: Contribution to journalArticlepeer-review

122 Scopus citations


The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.

Original languageEnglish
Pages (from-to)1059-1073
Number of pages15
Issue number5
StatePublished - Mar 2 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

ASJC Scopus subject areas

  • General Neuroscience


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