Abstract
Research on endocannabinoid signaling has greatly advanced our understanding of how the excitability of neural circuits is controlled in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses excitability by inhibiting glutamate release, while that at inhibitory synapses promotes excitability by inhibiting GABA release, although there are some exceptions in genetically epileptic animal models. In the epileptic brain, the physiological distributions of endocannabinoid signaling molecules are disrupted during epileptogenesis, contributing to the occurrence of spontaneous seizures. However, it is still unknown how endocannabinoid signaling changes during seizures and how the redistribution of endocannabinoid signaling molecules proceeds during epileptogenesis. Recent development of cannabinoid sensors has enabled us to investigate endocannabinoid signaling in much greater spatial and temporal details than before. Application of cannabinoid sensors to epilepsy research has elucidated activity-dependent changes in endocannabinoid signaling during seizures. Furthermore, recent endocannabinoid research has paved the way for the clinical use of cannabidiol for the treatment of refractory epilepsy, such as Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Cannabidiol significantly reduces seizures and is considered to have comparable tolerability to conventional antiepileptic drugs. In this article, we introduce recent advances in research on the roles of endocannabinoid signaling in epileptic seizures and discuss future directions.
Highlights
Epilepsy is one of the most common neurological disorders, with an incidence of 50.4 per 100,000 people per year (Ngugi et al, 2011)
No significant effect was observed on DSE in CA1 pyramidal neurons at 5 weeks after the febrile seizures (Chen et al, 2003). These results suggest that neonatal febrile seizures change the expression pattern of CB1 receptors in the hippocampus during development and promote disinhibition of hippocampal neural circuits, which might contribute to epileptogenesis
A single intraperitoneal injection of the CB1 antagonist SR141716A (1 mg/kg, i.p.) into rat pups 1 h before the start of febrile seizures blocked the seizure-induced enhancement of DSI and increase of CB1 receptors in adults (Chen et al, 2007). These results indicate that CB1 receptor expression increases in the later stage of SE- or febrile seizureinduced epileptogenesis, which can be blocked by CB1 receptor antagonists before febrile seizures
Summary
Epilepsy is one of the most common neurological disorders, with an incidence of 50.4 per 100,000 people per year (Ngugi et al, 2011). Activation of Gq/11 coupled-receptors in neurons releases endocannabinoids that retrogradely act on presynaptic CB1 receptors and induce transient synaptic suppression (Maejima et al, 2001; Varma et al, 2001). Soon after these discoveries, endocannabinoid-mediated long-term suppression of synaptic transmission was reported (Gerdeman et al, 2002; Marsicano et al, 2002; Robbe et al, 2002). CB1 receptor-dependent STD occurs when a postsynaptic neuron is strongly depolarized and the intracellular Ca2+ level increases following Ca2+ influx through voltage-gated calcium channels This STD of excitatory or inhibitory synaptic transmission is called depolarization-induced suppression of excitation (DSE) or inhibition (DSI), respectively. The effects of CB2 receptor signaling on neuronal network activity differ depending on brain areas and cell types
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