6533b826fe1ef96bd1283c71

RESEARCH PRODUCT

Cannabinoid Control of Learning and Memory through HCN Channels

Anh BuiAnh BuiSang-hun LeeBeat LutzHannah K. KimHannah K. KimIvan SolteszMattia MarosoMattia MarosoGergely G. SzaboGergely G. SzaboAllyson Alexander

subject

0301 basic medicineMAP Kinase Kinase 4medicine.medical_treatmentMorpholinesNeuroscience(all)RegulatorMice TransgenicBiologyNaphthalenesHippocampusBiophysical PhenomenaArticleMembrane Potentials03 medical and health sciencesMice0302 clinical medicineReceptor Cannabinoid CB1medicineHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsAnimalsEnzyme InhibitorsReceptorCyclic GMPSpatial MemoryMembrane potentialNeuronsGeneral NeuroscienceLong-term potentiationDendritesSynaptic PotentialsCalcium Channel BlockersBenzoxazines030104 developmental biologyMutationExcitatory postsynaptic potentialCannabinoidSignal transductionNitric Oxide SynthaseNeuroscience030217 neurology & neurosurgeryIntracellularSignal Transduction

description

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.

yearjournalcountryeditionlanguage
2016-03-01Neuron
10.1016/j.neuron.2016.01.023http://dx.doi.org/10.1016/j.neuron.2016.01.023