Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy

Because molecular mechanisms underlying refractory focal epilepsy are poorly defined, we performed transcriptome analysis on human epileptogenic tissue. Compared with controls, expression of Circadian Locomotor Output Cycles Kaput (CLOCK) is decreased in epileptogenic tissue. To define the function of CLOCK, we generated and tested the Emx-Cre; Clock^flox/flox and PV-Cre; Clock^flox/flox mouse lines with targeted deletions of the Clock gene in excitatory and parvalbumin (PV)-expressing inhibitory neurons, respectively. The Emx-Cre; Clock^flox/flox mouse line alone has decreased seizure thresholds, but no laminar or dendritic defects in the cortex. However, excitatory neurons from the Emx-Cre; Clock^flox/flox mouse have spontaneous epileptiform discharges. Both neurons from Emx-Cre; Clock^flox/flox mouse and human epileptogenic tissue exhibit decreased spontaneous inhibitory postsynaptic currents. Finally, video-EEG of Emx-Cre; Clock^flox/flox mice reveals epileptiform discharges during sleep and also seizures arising from sleep. Altogether, these data show that disruption of CLOCK alters cortical circuits and may lead to generation of focal epilepsy. Li, Fu, et al. find that expression of the circadian transcription factor CLOCK is decreased in the “seizure focus” from patients with intractable epilepsy and that CLOCK loss of function in cortical excitatory neurons is sufficient for epileptogenesis in mouse.