Epileptic seizures are the manifestation of hypersynchronous and excessive neuronal excitation. While the glutamatergic and GABAergic neurons play major roles in shaping fast neuronal excitation/inhibition homeostasis, it is well illustrated that astrocytes profoundly regulate neuronal excitation by controlling glutamate, GABA, cannabinoids, adenosine and concentration of K+ around neurons. However, little is known whether microglia take part in the regulation of acute neuronal excitation and ongoing epileptic behaviors. We proposed that if microglia are innately ready to respond to epileptic overexcitation, depletion of microglia might alter neuronal excitability and severity of acute epileptic seizures. We found that microglia depletion by PLX3397, an inhibitor of CSF1R, exacerbates seizure severity and excitotoxicity-induced neuronal degeneration, indicating that microglia are rapidly responsive to the change of excitation/inhibition homeostasis and participate in the protection of neurons from overexcitation.

Cannabinoids (CBs), such as phytocannabinoids, synthetic CBs, and endogenous CBs, can be neuroprotective, rewarding, or aversive. The aversive effects of CBs may hinder their medical and recreational applications. It is unknown which type of CB receptors mediates the direct aversive effects of synthetic CB CP 55,940 which is an analog of Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana. In this study, we address this question by taking the advantage of systematic type 1 CB receptor (CB1R) knockout mice and conditional reinstatement of this receptor only in astrocytes. We show that CP 55,940 at a concentration of 1 mg/kg induces conditioned place aversion (CPA) and the CPA effect of CP 55,940 is mediated by the astroglial CB1Rs. Inhibiting cyclooxygenase-2 (COX-2) eliminates CP 55,940-induced CPA in mice that only express CB1Rs in astrocytes. These findings conclude that CPA effect of CP 55,940 is mediated by the astroglial CB1Rs through COX-2 signaling, suggesting that selective COX-2 inhibition or precise isolation of astroglial CB1R activity may be the strategy for treating aversive response of medical and recreational administrations of marijuana.

Status epilepticus (SE) is a medical emergency associated with acute severe systemic damage and high mortality. Moreover, symptomatic SE is one of the highest risk factors for epileptogenesis. While the antiepileptic drugs (AEDs) are chosen in favor of acute control of SE, the potential short-term and long-term effects of such AEDs have been ignored in clinics. In this study, we hypothesized that AEDs that are used to control acute SE might affect the feasibility for the chronic development of epileptogenesis after SE. Therefore, we sought to compare the epileptogenic effects of SE that are terminated by three AEDs, i.e., diazepam, midazolam, and pentobarbital, which are widely used as first-line anti-SE AEDs. For this purpose, we used a mouse model of SE induced by intraperitoneal (i.p.) injection of lithium chloride (LiCl)-pilocarpine. The pilocarpine-induced SE was terminated with diazepam, midazolam, or pentobarbital. Then we compared short-term and long-term effects of SE with different AED treatments by examining SE-associated mortality and behavioral spontaneous recurrent seizures (SRSs) and by using magnetic resonance imaging (MRI) and immunohistochemistry to evaluate pathological and cellular alterations of mice in the different treatment groups. We found that i.p. injections of diazepam (5 mg/kg), midazolam (10 mg/kg), and pentobarbital (37.5 mg/kg) were able to terminate acute pilocarpine-SE effectively, while pentobarbital treatment showed less neuroprotective action against lethality in the short phase following SE. Long-term evaluation following SE revealed that SE treated with midazolam had resulted in relatively less behavioral SRS, less hippocampal atrophy, and milder neuronal loss and gliosis. Our data revealed an obvious advantage of midazolam vs. diazepam or pentobarbital in protecting the brain from epileptogenesis. Therefore, if midazolam provides as strong action to quench SE as other AEDs in clinics, midazolam should be the first choice of anti-SE AEDs as it provides additional benefits against epileptogenesis.