Editors' ChoiceEpilepsy

Epilepsy clocks in

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Science Translational Medicine  15 Nov 2017:
Vol. 9, Issue 416, eaaq1237
DOI: 10.1126/scitranslmed.aaq1237

Abstract

Circadian CLOCK gene expression is reduced in human epileptic brain tissue, and its deletion is epileptogenic in mice.

Epilepsy is a common neurological condition marked by recurrent, unprovoked seizures. Although recent progress has identified single gene mutations leading to generalized, inherited forms of epilepsy, the vast majority of epilepsy patients suffer from focal seizures originating in discrete brain regions. Surgical resection of the area where seizures originate is often successful for ameliorating pharmaco-resistant epilepsies; however, a better understanding of the molecular mechanisms leading to disease pathogenesis in these types of lesions is critical to develop more effective and less invasive therapies. Here, Li et al. performed transcriptome analyses on epileptic tissue obtained from patients with focal cortical dysplasia and tuberous sclerosis complex to identify molecular signatures of epileptogenicity, and they validated the results in experimental models.

The team obtained fresh surgical specimens from epileptic patients who had undergone therapeutic resections of the epileptogenic area. The location and extent of the epileptogenic tissue was defined by magnetic resonance imaging, followed by intraoperative electrocorticography. Radiologically normal control samples without epileptiform activity were obtained from unaffected brain regions of epileptic patients, requiring tissue removal to access deeper brain structures. Microarray transcriptome analyses revealed decreased mRNA expression of the Circadian Locomotor Output Cycles Kaput (CLOCK) gene encoding CLOCK, a transcription factor critically involved in generation of circadian rhythms. These findings were further confirmed by protein assays for CLOCK and its downstream signaling components Cryptochrome (Cry) and Period (Per) in epileptogenic samples. CLOCK expression was diminished in both excitatory and inhibitory cortical neurons from epileptogenic tissue. Leveraging mouse genetic approaches to test for cell type specificity, the team made the remarkable, unexpected discovery that although Clock deletion in inhibitory neurons did not influence seizure thresholds or cause spontaneous seizures, the deletion in excitatory neurons decreased seizure thresholds and triggered spontaneous seizures. Cortical lamination and dendritic branching appeared unchanged in the knockout mice. However, Clock deletion decreased dendritic spine formation and impaired spine maintenance. These effects were accompanied by disrupted inhibitory postsynaptic currents, leading to frequent polyspike events, which are cellular correlates of epileptiform discharges. Overall, CLOCK loss of function in primary neurons resulted in increased excitation in cortical circuits, culminating in animals with frequent interictal epileptiform discharges and tonic-clonic seizures during sleep. Notably, nearly 25% of epilepsy patients have seizures during sleep, and nocturnal seizures are an independent risk factor for sudden unexpected death in epilepsy. The CLOCK-associated circuit changes will need to be further elucidated in human epilepsy. However, together with recent advances coupling circadian rhythmicity to protein synthesis, this new study provides a suite of testable molecular pathways to improve our understanding of the brain’s microcircuitry in common forms of epilepsy.

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