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The Journal of Neuroscience, January 3, 2007, 27(1):46-58; doi:10.1523/JNEUROSCI.3966-06.2007

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Neurobiology of Disease
Prevention of Plasticity of Endocannabinoid Signaling Inhibits Persistent Limbic Hyperexcitability Caused by Developmental Seizures

Kang Chen,¹ Axel Neu,¹ Allyson L. Howard,¹ Csaba Földy,¹ Julio Echegoyen,¹ Lutz Hilgenberg,¹ Martin Smith,¹ Ken Mackie,² and Ivan Soltesz¹

¹Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, and ²Department of Anesthesiology, University of Washington, Seattle, Washington 98195

Correspondence should be addressed to Dr. Ivan Soltesz, Anatomy and Neurobiology, University of California, Irvine, CA 92697-1280. Email: isoltesz{at}uci.edu

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.

Key words: cannabinoid; inhibition; plasticity; seizure; development; hippocampus

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Received Sept. 12, 2006; revised Oct. 27, 2006; accepted Nov. 22, 2006.

Correspondence should be addressed to Dr. Ivan Soltesz, Anatomy and Neurobiology, University of California, Irvine, CA 92697-1280. Email: isoltesz{at}uci.edu

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