Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy.
Temporal lobe epilepsy (TLE) is a condition characterized by an imbalance between excitation and inhibition in the temporal lobe. Hallmarks of this change are axon sprouting and accompanying synaptic reorganization in the temporal lobe. Synthetic and endogenous cannabinoids have variable therapeutic potential in treating intractable temporal lobe epilepsy, in part because cannabinoid ligands can bind multiple receptor types. This study utilized in vitro electrophysiological methods to examine the effect of transient receptor potential vanilloid type 1 (TRPV1) activation in dentate gyrus granule cells in a murine model of TLE. Capsaicin, a selective TRPV1 agonist had no measurable effect on overall synaptic input to granule cells in control animals, but significantly enhanced spontaneous and miniature EPSC frequency in mice with TLE. Exogenous application of anandamide, an endogenous cannabinoid that acts at both TRPV1 and cannabinoid type 1 receptors (CB1R), also enhanced glutamate release in the presence of a CB1R antagonist. Anandamide reduced the EPSC frequency when TRPV1 were blocked with capsazepine. Western blot analysis of TRPV1 receptor indicated protein expression was significantly greater in the dentate gyrus of mice with TLE compared with control mice. This study indicates that a prominent cannabinoid agonist can increase excitatory circuit activity in the synaptically reorganized dentate gyrus of mice with TLE by activating TRPV1 receptors, and suggests caution in designing anticonvulsant therapy based on modulating the endocannabinoid system.
Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118, USA.
Muthu D
MD
Bhaskaran
Bret N
BN
Smith
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D015195:Drug Design; D063388:Endocannabinoids; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000502:physiology; D018721:Muscarinic Agonists / Q000633:toxicity; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010862:Pilocarpine / Q000633:toxicity; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000502:physiology; D018689:Sensory System Agents / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D050916:TRPV Cation Channels / Q000819:agonists / Q000502:physiology*
D000927:Anticonvulsants; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D018721:Muscarinic Agonists; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D010862:Pilocarpine; D002211:Capsaicin; C078814:anandamide