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

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

Neuroscience

Research output: Contribution to journal › Article › peer-review

109 Scopus citations

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 (I_h), 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 I_h 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 I_h or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-I_h pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.

Original language	English
Pages (from-to)	1059-1073
Number of pages	15
Journal	Neuron
Volume	89
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2016.01.023
State	Published - Mar 2 2016

Bibliographical note

Funding Information:
We thank K. Mackie for providing JNK KO mice; S. Siegelbaum for providing the forebrain-restricted HCN1KO mice; G. Marsicano for providing the GLU-, GABA-, and global-CB1RKO mice; and T. Nguyen and S. Felong for technical support. This work was supported by the U.S. National Institutes of Health (NS35915 and NS94668 to I.S., F31NS086429 to A.B., and R25NS065741-04S1 to A.A.), the National Aeronautics and Space Administration (NSCOR NNX10AD59G to I.S.), and by a European Molecular Biology Organization (EMBO) long-term fellowship to M.M.

Funding Information:
We thank K. Mackie for providing JNK KO mice; S. Siegelbaum for providing the forebrain-restricted HCN1KO mice; G. Marsicano for providing the GLU-, GABA-, and global-CB1RKO mice; and T. Nguyen and S. Felong for technical support. This work was supported by the U.S. National Institutes of Health (NS35915 and NS94668 to I.S., F31NS086429 to A.B., and R25NS065741-04S1 to A.A.), the National Aeronautics and Space Administration (NSCOR NNX10AD59G to I.S.), and by a European Molecular Biology Organization (EMBO) long-term fellowship to M.M.

Publisher Copyright:
© 2016 Elsevier Inc.

ASJC Scopus subject areas

Neuroscience (all)

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10.1016/j.neuron.2016.01.023

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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.",

author = "Mattia Maroso and Szabo, {Gergely G.} and Kim, {Hannah K.} and Allyson Alexander and Bui, {Anh D.} and Lee, {Sang Hun} and Beat Lutz and Ivan Soltesz",

note = "Funding Information: We thank K. Mackie for providing JNK KO mice; S. Siegelbaum for providing the forebrain-restricted HCN1KO mice; G. Marsicano for providing the GLU-, GABA-, and global-CB1RKO mice; and T. Nguyen and S. Felong for technical support. This work was supported by the U.S. National Institutes of Health (NS35915 and NS94668 to I.S., F31NS086429 to A.B., and R25NS065741-04S1 to A.A.), the National Aeronautics and Space Administration (NSCOR NNX10AD59G to I.S.), and by a European Molecular Biology Organization (EMBO) long-term fellowship to M.M. Funding Information: We thank K. Mackie for providing JNK KO mice; S. Siegelbaum for providing the forebrain-restricted HCN1KO mice; G. Marsicano for providing the GLU-, GABA-, and global-CB1RKO mice; and T. Nguyen and S. Felong for technical support. This work was supported by the U.S. National Institutes of Health (NS35915 and NS94668 to I.S., F31NS086429 to A.B., and R25NS065741-04S1 to A.A.), the National Aeronautics and Space Administration (NSCOR NNX10AD59G to I.S.), and by a European Molecular Biology Organization (EMBO) long-term fellowship to M.M. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

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AU - Szabo, Gergely G.

AU - Kim, Hannah K.

AU - Alexander, Allyson

AU - Bui, Anh D.

AU - Lee, Sang Hun

AU - Lutz, Beat

AU - Soltesz, Ivan

N1 - Funding Information: We thank K. Mackie for providing JNK KO mice; S. Siegelbaum for providing the forebrain-restricted HCN1KO mice; G. Marsicano for providing the GLU-, GABA-, and global-CB1RKO mice; and T. Nguyen and S. Felong for technical support. This work was supported by the U.S. National Institutes of Health (NS35915 and NS94668 to I.S., F31NS086429 to A.B., and R25NS065741-04S1 to A.A.), the National Aeronautics and Space Administration (NSCOR NNX10AD59G to I.S.), and by a European Molecular Biology Organization (EMBO) long-term fellowship to M.M. Funding Information: We thank K. Mackie for providing JNK KO mice; S. Siegelbaum for providing the forebrain-restricted HCN1KO mice; G. Marsicano for providing the GLU-, GABA-, and global-CB1RKO mice; and T. Nguyen and S. Felong for technical support. This work was supported by the U.S. National Institutes of Health (NS35915 and NS94668 to I.S., F31NS086429 to A.B., and R25NS065741-04S1 to A.A.), the National Aeronautics and Space Administration (NSCOR NNX10AD59G to I.S.), and by a European Molecular Biology Organization (EMBO) long-term fellowship to M.M. Publisher Copyright: © 2016 Elsevier Inc.

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N2 - 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.

AB - 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.

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JO - Neuron

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Cannabinoid Control of Learning and Memory through HCN Channels

Abstract

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