Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures

TY - JOUR

T1 - Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures

AU - Chen, Kang

AU - Neu, Axel

AU - Howard, Allyson L

AU - Földy, Csaba

AU - Echegoyen, Julio

AU - Hilgenberg, Lutz

AU - Smith, Martin

AU - Mackie, Ken

AU - Soltesz, Ivan

PY - 2007/1/3

Y1 - 2007/1/3

N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Limbic System

KW - Long-Term Potentiation

KW - Neural Inhibition

KW - Neuronal Plasticity

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptor, Cannabinoid, CB1

KW - Seizures, Febrile

KW - Signal Transduction

U2 - 10.1523/JNEUROSCI.3966-06.2007

DO - 10.1523/JNEUROSCI.3966-06.2007

M3 - SCORING: Journal article

C2 - 17202471

VL - 27

SP - 46

EP - 58

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 1

ER -