title: Cannabinoid Control of Learning and Memory through HCN Channels.
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.
authors.affiliation: 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.
authors.forename: Mattia
authors.initials: M
authors.lastname: Maroso
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Gergely G
authors.initials: GG
authors.lastname: Szabo
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
authors.forename: Allyson
authors.initials: A
authors.lastname: Alexander
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Anh D
authors.initials: AD
authors.lastname: Bui
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128 Mainz, Germany.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Soltesz
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D003712:Dendrites / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics*
chemical_list: D048588:Benzoxazines; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D019001:Nitric Oxide Synthase; D048670:MAP Kinase Kinase 4; D006152:Cyclic GMP