Binge drinking (BD) is a serious health concern in adolescents as high ethanol (EtOH) consumption can have cognitive sequelae later in life. Remarkably, an enriched environment (EE) in adulthood significantly recovers memory in mice after adolescent BD, and the endocannabinoid, 2-arachydonoyl-glycerol (2-AG), rescues synaptic plasticity and memory impaired in adult rodents upon adolescent EtOH intake. However, the mechanisms by which EE improves memory are unknown. We investigated this in adolescent male C57BL/6J mice exposed to a drinking in the dark (DID) procedure four days per week for a duration of 4 weeks. After DID, the mice were nurtured under an EE for 2 weeks and were subjected to the Barnes Maze Test performed the last 5 days of withdrawal. The EE rescued memory and restored the EtOH-disrupted endocannabinoid (eCB)-dependent excitatory long-term depression at the dentate medial perforant path synapses (MPP-LTD). This recovery was dependent on both the cannabinoid CB1 receptor and group I metabotropic glutamate receptors (mGluRs) and required 2-AG. Also, the EE had a positive effect on mice exposed to water through the transient receptor potential vanilloid 1 (TRPV1) and anandamide (AEA)-dependent MPP long-term potentiation (MPP-LTP). Taken together, EE positively impacts different forms of excitatory synaptic plasticity in water- and EtOH-exposed brains.

Epilepsy is one of the most common neurological conditions. Yearly, five million people are diagnosed with epileptic-related disorders. The neuroprotective and therapeutic effect of (endo)cannabinoid compounds has been extensively investigated in several models of epilepsy. Therefore, the study of specific cell-type-dependent mechanisms underlying cannabinoid effects is crucial to understanding epileptic disorders. It is estimated that about 100 billion neurons and a roughly equal number of glial cells co-exist in the human brain. The glial population is in charge of neuronal viability, and therefore, their participation in brain pathophysiology is crucial. Furthermore, glial malfunctioning occurs in a wide range of neurological disorders. However, little is known about the impact of the endocannabinoid system (ECS) regulation over glial cells, even less in pathological conditions such as epilepsy. In this review, we aim to compile the existing knowledge on the role of the ECS in different cell types, with a particular emphasis on glial cells and their impact on epilepsy. Thus, we propose that glial cells could be a novel target for cannabinoid agents for treating the etiology of epilepsy and managing seizure-like disorders.

Prolonged neurotransmitter release following synaptic stimulation extends the time window for postsynaptic neurons to respond to presynaptic activity. This can enhance excitability and increase synchrony of outputs, but the prevalence of this at normally highly synchronous synapses is unclear. We show that the postsynaptic channel, pannexin-1 (Panx1) regulates prolonged glutamate release onto CA1 neurons. Block of postsynaptic (CA1 neuronal) Panx1 increased the frequency of glutamate neurotransmission and action potentials in these neurons following Schaffer collateral stimulation. When Panx1 was blocked, anandamide levels increase and activated transient receptor potential vanilloid 1 (TRPV1)-mediated glutamate release. This TRPV1-induced synaptic acitvity enhanced excitability and translated into a faster rate of TRPV1-dependent epileptogenesis induced by kindling. We conclude that Panx1 facilitates AEA clearance to maintain synchronous release onto CA1 neurons so that when AEA clearance is reduced, TRPV1 channels prolong glutamate neurotransmission to enhance network output to promote epileptiform activity.

Background: Navigation and memory are hippocampal functions that are essential for survival. One of the key modulators of hippocampal activity is the endocannabinoid system through the cannabinoid receptor type 1 (CB1). CB1 is widely expressed in various types of hippocampal cells. While it is known that CB1 participates in memory processes, its specific roles in different cell types and differences between sexes remain unclear. Methods: This study investigates the cell- and sex-specific modulation of navigation and memory by CB1 receptors. To this end, we selectively deleted CB1 receptors from hippocampal neurons or astrocytes in adult male and female mice. We then assessed its effect on a comprehensive range of behaviors, including innate emotional responses, memory, navigation, and nesting. Results: Deletion of CB1 from hippocampal principal cells or astrocytes produced significant changes in innate emotional behavior and novel object recognition in both sexes. Conversely, CB1 receptor deletion from all neurons produced deficits in spatial navigation exclusively in males. Interestingly, synaptic plasticity was impaired in both male and female mice lacking CB1 receptors from GFAP-positive cells. Nest-building behavior was only affected in males carrying the CB1 deletion in CAMK-positive cells. Conclusion: In conclusion, our findings show that neuronal CB1 receptors are critical for spatial navigation in males, while astrocytic CB1 receptors play a key role in memory processes in both males and females.