Cannabinoid Receptor Type 1 (CB1R) Expression in Limbic Brain Structures After Acute and Chronic Seizures in a Genetic Model of Epilepsy

Abstract

The endocannabinoid system (ECS) is related to several physiological processes, associated to the modulation of brain excitability, with impact in the expression of susceptibility and control of epileptic seizures. The cannabinoid receptor type 1 (CB1R) is widely expressed in the brain, especially in forebrain limbic structures. Changes in CB1R expression are associated with epileptic seizures in animal models and humans. The Wistar Audiogenic Rat (WAR) strain is a genetic model of epilepsy capable of mimicking tonic-clonic and limbic seizures in response to intense sound stimulation. The WAR strain presents several behavioral and physiological alterations associated with seizure susceptibility, but the ECS has never been explored in this strain. Therefore, the aim of the present study was to characterize CB1R expression in forebrain limbic structures important to limbic seizure expression in WARs. We used a detailed anatomical analysis to assess the effects of acute and chronic audiogenic seizures on CB1R expression in several layers and regions of hippocampus and amygdala. WARs showed increased CB1R immunostaining in the inner molecular layer of the hippocampus, when compared to control Wistar rats. Acute and chronic audiogenic seizures increased CB1R immunostaining in several regions of the dorsal hippocampus and amygdala of WARs. Also, changes in CB1R expression in the amygdala, but not in the hippocampus, were associated with limbic recruitment and limbic seizure severity in WARs. Our results suggest that endogenous alterations in CB1R immunostaining in WARs could be associated with genetic susceptibility to audiogenic seizures. We also demonstrated CB1R neuroplastic changes associated with acute and chronic seizures in the amygdala and hippocampus. Moreover, the present study brings important information regarding CB1R and seizure susceptibility in a genetic model of seizures and supports the relationship between ECS and epilepsy.

Distribution of the Cannabinoid Receptor Type 1 in the Brain of the Genetically Audiogenic Seizure-Prone Hamster GASH/Sal

“…Additionally, in the Wistar audiogenic rat strain (WAR), a genetic model of audiogenic epilepsy, exhibit and endogenous increase of CB1R immunostaining in the hippocampus and amygdala after acute and chronic audiogenic seizures (Lazarini-Lopes et al, 2020b). These recent data reinforce the link between the limbic system and seizure susceptibility and provide new knowledge on the role of the endocannabinoid system in the control of neuronal excitability.…”

“…The increase of Cb1r expression in the hippocampus, and in the amygdala, has been described in other epileptic animal models (Lazarini-Lopes et al, 2020b). It has been postulated that this constitutive increase in endocannabinoids in animal models of epilepsy could have a possible neuroprotective mechanism (via decreasing excitability and synchronization by reducing glutamate and GABA release) (Guggenhuber et al, 2010;Goffin et al, 2011).…”

Cannabinoids in Audiogenic Seizures: From Neuronal Networks to Future Perspectives for Epilepsy Treatment

“…Acute AS also induced changes in CB1R in the central and medial amygdala nuclei. Moreover, it is worth to note that, changes in CB1R expression in lateral, basolateral, and basomedial amygdala nuclei were correlated with limbic seizure severity during the AuK (Lazarini-Lopes et al, 2020a). See Figure 1 for a representative view of CB1R expression in limbic and cortical structures of audiogenic susceptible rats from the WAR strain.…”

Endocannabinoid-Mediated Control of Neural Circuit Excitability and Epileptic Seizures

“…One of the most important discoveries in the field of cannabinoid research is the discovery that endocannabinoids function as a retrograde messenger at synapses-endocannabinoids mediate signals from depolarized postsynaptic neurons to presynaptic CB 1 receptors, leading to a transient suppression of synaptic transmission (Kreitzer and Regehr, 2001;Ohno-Shosaku et al, 2001;Wilson and Nicoll, 2001). Furthermore, activation of G q/11 coupled-receptors in neurons releases endocannabinoids that retrogradely act on presynaptic CB 1 receptors and induce transient synaptic suppression (Maejima et al, 2001;Varma et al, 2001).…”

“…In a mouse model of Dravet syndrome wherein the mice carry a missense mutation (A1783V) in the Scn1a gene that encodes the α subunit of a voltage-gated sodium channel, decreased CB 1 but increased CB 2 receptor expression was reported in the hippocampus by western blotting analysis ( Satta et al, 2020 ). In contrast, in Wister audiogenic rats, CB 1 receptor expression in the hippocampus and amygdala was found to be increased after acute and chronic audiogenic seizures induced by sound stimulation (110–120 dB, 5–20 kHz, 60 s maximum) ( Lazarini-Lopes et al, 2020 ). Taken together, these results indicate that the pattern of CB 1 expression and its changes with age or in response to seizures differ greatly in different genetically epileptic rodent models.…”