title: Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.
abstract: Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, long-term plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarization-induced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced long-term hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo fever-induced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.forename: Axel
authors.initials: A
authors.lastname: Neu
authors.forename: Allyson L
authors.initials: AL
authors.lastname: Howard
authors.forename: Csaba
authors.initials: C
authors.lastname: Földy
authors.forename: Julio
authors.initials: J
authors.lastname: Echegoyen
authors.forename: Lutz
authors.initials: L
authors.lastname: Hilgenberg
authors.forename: Martin
authors.initials: M
authors.lastname: Smith
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Ivan
authors.initials: I
authors.lastname: Soltesz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D008032:Limbic System / Q000503:physiopathology*; D017774:Long-Term Potentiation; D009433:Neural Inhibition; D009473:Neuronal Plasticity; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D003294:Seizures, Febrile / Q000503:physiopathology*; D015398:Signal Transduction
chemical_list: D043884:Receptor, Cannabinoid, CB1