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

doi:10.1016/j.neuron.2016.01.023

Cannabinoid Control of Learning and Memory through HCN Channels

Neuron. 2016 Mar 2;89(5):1059-73. doi: 10.1016/j.neuron.2016.01.023. Epub 2016 Feb 18.

Authors

Mattia Maroso¹, Gergely G Szabo², Hannah K Kim², Allyson Alexander³, Anh D Bui², Sang-Hun Lee⁴, Beat Lutz⁵, Ivan Soltesz³

Affiliations

¹ Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: mmaroso@stanford.edu.
² Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
³ Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
⁵ Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128 Mainz, Germany.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Benzoxazines / pharmacology
Biophysical Phenomena / drug effects
Biophysical Phenomena / genetics
Calcium Channel Blockers / pharmacology
Cyclic GMP / metabolism
Dendrites / physiology
Enzyme Inhibitors / pharmacology
Hippocampus / cytology
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism*
MAP Kinase Kinase 4 / genetics
MAP Kinase Kinase 4 / metabolism
Membrane Potentials / drug effects
Membrane Potentials / genetics
Mice
Mice, Transgenic
Morpholines / pharmacology
Mutation / genetics
Naphthalenes / pharmacology
Neurons / cytology
Neurons / drug effects
Neurons / metabolism
Nitric Oxide Synthase / metabolism
Receptor, Cannabinoid, CB1 / genetics
Receptor, Cannabinoid, CB1 / metabolism*
Signal Transduction / genetics
Signal Transduction / radiation effects
Spatial Memory / drug effects
Spatial Memory / physiology*
Synaptic Potentials / drug effects
Synaptic Potentials / genetics*

Substances

Benzoxazines
Calcium Channel Blockers
Enzyme Inhibitors
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Morpholines
Naphthalenes
Receptor, Cannabinoid, CB1
(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
Nitric Oxide Synthase
MAP Kinase Kinase 4
Cyclic GMP

Abstract

Publication types

MeSH terms

Substances

Grants and funding