The Endocannabinoid System Activation as a Neural Network Desynchronizing Mediator for Seizure Suppression

The understanding that hyper-excitability and hyper-synchronism in epilepsy are indissociably bound by a cause-consequence relation has only recently been challenged. Thus, therapeutic strategies for seizure suppression have often aimed at inhibiting excitatory circuits and/or activating inhibitory ones. However, new approaches that aim to desynchronize networks or compromise abnormal coupling between adjacent neural circuitry have been proven effective, even at the cost of enhancing local neuronal activation. Although most of these novel perspectives targeting circuitry desynchronization and network coupling have been implemented by non-pharmacological devices, we argue that there may be endogenous neurochemical systems that act primarily in the desynchronization component of network behavior rather than dampening excitability of individual neurons. This review explores the endocannabinoid system as one such possible pharmacological landmark for mimicking a form of “on-demand” desynchronization analogous to those proposed by deep brain stimulation in the treatment of epilepsy. This essay discusses the evidence supporting the role of the endocannabinoid system in modulating the synchronization and/or coupling of distinct local neural circuitry; which presents obvious implications on the physiological setting of proper sensory-motor integration. Accordingly, the process of ictogenesis involves pathological circuit coupling that could be avoided, or at least have its spread throughout the containment of other areas, if such endogenous mechanisms of control could be activated or potentiated by pharmacological intervention. In addition, we will discuss evidence that supports not only a weaker role played on neuronal excitability but the potential of the endocannabinoid system strengthening its modulatory effect, only when circuitry coupling surpasses a level of activation.