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 Ca 2ϩ 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, longterm plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarizationinduced 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 longterm hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo feverinduced (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.

Cannabinoids and Epilepsy

“…CBDV potentiated the effects of phenobarbital, ethosuximide, and valproate in 2 seizure models [181]. These studies suggest that both Δ9-THC and CBD provide significant protection from seizures [147,[154][155][156][157][158][159][160][161][162][163][164][165][166]. GABA = γ-aminobutryic acid in preclinical animal trials, presenting potential targets for human studies.…”

“…This finding suggests that patients with prolonged, pharmacoresistant epilepsy may suffer from impaired CB 1 R homeostasis on inhibitory interneuron terminals, leading to prolonged disinhibition and network excitability. Postseizure changes in CB 1 Rs may be specific to seizure type or developmental stage, as mice with a single episode of febrile seizures induce an overall increase in DSI and CB 1 R on CCK+ interneurons [165,166]. Figure 4 summarizes the effects of synthetic cannabinoids and phytocannabinoids in 175 pre-clinical seizure models or discrete conditions (adapted from [167]).…”

Pharmacological Activation of Kainate Receptors Drives Endocannabinoid Mobilization

“…However, the regulation of GABAergic synaptic transmission by coactivation of CB 1 receptors and KARs could be relevant for other models of epilepsy. For instance, the modulation of GABA release by the ECS through activation of AMPA/KARs has been implicated in the control of persistent limbic hyperexcitability in several models of juvenile seizures (Chen et al, 2003(Chen et al, , 2007.…”

Cannabinoid-mediated short-term plasticity in hippocampus

“…A CB-mediated reduction in excitation during epileptiform activity would be expected to provide protection against excessive excitability whereas a reduction in inhibition would supposedly oppose this effect and result in pro-convulsant effect. Indeed, an upregulation of CB 1 receptors on GABAergic terminals but not on glutamatergic terminals has been observed due to febrile seizures, suggesting a pathological enhancement of DSI (Chen et al, 2007). Also, it has been hypothesised that suppression of excitation is the mode of action of the anti-convulsant effects of CBs (Blair, 2006;Hajos and Freund, 2002).…”