sr-8278 and Disease-Models--Animal

To design potentially more effective therapies, we need to further understand the mechanisms underlying epilepsy. Here, we uncover the role of Rev-erbα in circadian regulation of epileptic seizures. We first show up-regulation of REV-ERBα/Rev-erbα in brain tissues from patients with epilepsy and a mouse model. Ablation or pharmacological modulation of Rev-erbα in mice decreases the susceptibility to acute and chronic seizures, and abolishes diurnal rhythmicity in seizure severity, whereas activation of Rev-erbα increases the animal susceptibility. Rev-erbα 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-erbα-mediated clearance of GABA. Mechanistically, Rev-erbα promotes the expressions of Slc6a1 and Slc6a11 through transcriptional repression of E4bp4. Our findings propose Rev-erbα as a regulator of synaptic function at the crosstalk between pathways regulating the circadian clock and epilepsy.

Topics: Acute Disease; Animals; Basic-Leucine Zipper Transcription Factors; Chronic Disease; Disease Models, Animal; Epilepsy, Temporal Lobe; GABA Plasma Membrane Transport Proteins; GABAergic Neurons; gamma-Aminobutyric Acid; Gene Expression Regulation; Hippocampus; Humans; Inhibitory Postsynaptic Potentials; Isoquinolines; Kindling, Neurologic; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Subfamily 1, Group D, Member 1; RNA, Messenger; Seizures; Small Molecule Libraries; Thiophenes

A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; ARNTL Transcription Factors; Cell Line; Circadian Clocks; CLOCK Proteins; Disease Models, Animal; Isoquinolines; Macrophages; Mice; Mice, Knockout; Microglia; Nuclear Receptor Subfamily 1, Group D, Member 1; Plaque, Amyloid; Receptors, Cytoplasmic and Nuclear; Receptors, Purinergic P2Y12; Repressor Proteins; RNA, Small Interfering; Synapses; Thiophenes