Dysregulation Of Rev-Erb Alpha Impairs Gabaergic Function And Promotes Epileptic Seizures In Preclinical Models

To design potentially more effective therapies, we need to further understand the mechanisms underlying epilepsy. Here, we uncover the role of Rev-erb alpha in circadian regulation of epileptic seizures. We first show up-regulation of REV-ERB alpha/Rev-erb alpha in brain tissues from patients with epilepsy and a mouse model. Ablation or pharmacological modulation of Rev-erb alpha in mice decreases the susceptibility to acute and chronic seizures, and abolishes diurnal rhythmicity in seizure severity, whereas activation of Rev-erb alpha increases the animal susceptibility. Rev-erb alpha ablation or antagonism also leads to prolonged spontaneous inhibitory postsynaptic currents and elevated frequency in the mouse hippocampus, indicating enhanced GABAergic signaling. We also identify the transporters Slc6a1 and Slc6a11 as regulators of Rev-erb alpha-mediated clearance of GABA. Mechanistically, Rev-erb alpha promotes the expressions of Slc6a1 and Slc6a11 through transcriptional repression of E4bp4. Our findings propose Rev-erb alpha as a regulator of synaptic function at the crosstalk between pathways regulating the circadian clock and epilepsy.