2-AG-Mediated Control of GABAergic Signaling Is Impaired in a Model of Epilepsy

Abstract

Repeated seizures result in a persistent maladaptation of endocannabinoid (eCB) signaling, mediated part by anandamide signaling deficiency in the basolateral amygdala (BLA) that manifests as aberrant synaptic function and altered emotional behavior. Here, we determined the effect of repeated seizures (kindling) on 2-arachidonoylglycerol (2-AG) signaling on GABA transmission by directly measuring tonic and phasic eCB-mediated retrograde signaling in anin vitroBLA slice preparation from male rats. We report that both activity-dependent and muscarinic acetylcholine receptor (mAChR)-mediated depression of GABA synaptic transmission was reduced following repeated seizure activity. These effects were recapitulated in sham rats by preincubating slices with the 2-AG synthesizing enzyme inhibitor DO34. Conversely, preincubating slices with the 2-AG degrading enzyme inhibitor KML29 rescued activity-dependent 2-AG signaling, but not mAChR-mediated synaptic depression, over GABA transmission in kindled rats. These effects were not attributable to a change in cannabinoid type 1 (CB1) receptor sensitivity or altered 2-AG tonic signaling since the application of the highly selective CB1 receptor agonist CP55,940 provoked a similar reduction in GABA synaptic activity in both sham and kindled rats, while no effect of either DO34 or of the CB1 inverse agonist AM251 was observed on frequency and amplitude of spontaneous IPSCs in either sham or kindled rats. Collectively, these data provide evidence that repeated amygdala seizures persistently alter phasic 2-AG-mediated retrograde signaling at BLA GABAergic synapses, probably by impairing stimulus-dependent 2-AG synthesis/release, which contributes to the enduring aberrant synaptic plasticity associated with seizure activity.SIGNIFICANCE STATEMENTThe plastic reorganization of endocannabinoid (eCB) signaling after seizures and during epileptogenesis may contribute to the negative neurobiological consequences associated with seizure activity. Therefore, a deeper understanding of the molecular basis underlying the pathologic long-term eCB signaling remodeling following seizure activity will be crucial to the development of novel therapies for epilepsy that not only target seizure activity, but, most importantly, the epileptogenesis and the comorbid conditions associated with epilepsy.

Beneficial effects of gentiopicrin inhibiting experimental epilepsy in young rats through the P2X7R/NLRP3/Caspase-1 inflammatory pathway.

“…However, despite advances in the diagnosis and treatment of epilepsy, long-term use of antiepileptic drugs can lead to numerous adverse reactions. Furthermore, about 30% of children with epilepsy do not respond well to treatment, and severe cases can result into intractable epilepsy, which significantly af-fects the physical and mental health of patients 3 . Therefore, exploring the pathogenesis of epilepsy and finding new therapeutic drugs and targets are crucial for the effective treatment of this disorder.…”

Avaliação da associação de canabidiol e nitroprussiato de sódio no prejuízo sensório-motor induzido pelo tratamento agudo com MK-801

“…Os endocanabinoides são liberados dos neurônios de maneira dependente da atividade, agem retrogradamente nos receptores CB1 pré-sinápticos e induzem a supressão da liberação do neurotransmissor a curto ou longo prazo (para revisão, ARAQUE et al, 2017). A liberação de endocanabinóides que ativam receptores CB1 é desencadeada pela ativação pós-sináptica de canais de Ca2+ dependentes de voltagem e/ou receptores acoplados a Gq, como os receptores metabotrópicos de glutamato do grupo I (I-mGluRs; KUSHMERICK et al, 2004;OHNO-SHOSAKU et al, 2002;YOSHIDA et al, 2002) e os receptores muscarínicos M1 ou M3 (COLANGELI et al, 2022;FUKUDOME et al, 2004). Esses dados indicam que a ativação dos receptores NMDA facilita a liberação de endocanabinoides isoladamente ou em conjunto com os receptores acoplados a Gq (OHNO-SHOSAKU et al, 2007).…”