Prevention of Plasticity of Endocannabinoid Signaling Inhibits Persistent Limbic Hyperexcitability Caused by Developmental Seizures
Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca 2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergi...
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| Main Authors: | , , , , , , , , |
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| 格式: | Artigo |
| 語言: | 英语 |
| 出版: |
2007
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| 在線閱讀: | https://doi.org/10.1523/jneurosci.3966-06.2007 https://www.jneurosci.org/content/jneuro/27/1/46.full.pdf |
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| 總結: | Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca 2+ 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. |
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