Dataset Information

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

ABSTRACT: 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; Clockflox/flox and PV-Cre; Clockflox/flox mouse lines with targeted deletions of the Clock gene in excitatory and parvalbumin (PV)-expressing inhibitory neurons, respectively. The Emx-Cre; Clockflox/flox mouse line alone has decreased seizure thresholds, but no laminar or dendritic defects in the cortex. However, excitatory neurons from the Emx-Cre; Clockflox/flox mouse have spontaneous epileptiform discharges. Both neurons from Emx-Cre; Clockflox/flox mouse and human epileptogenic tissue exhibit decreased spontaneous inhibitory postsynaptic currents. Finally, video-EEG of Emx-Cre; Clockflox/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.

SUBMITTER: Li P

PROVIDER: S-EPMC6233318 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Li Peijun P Fu Xiaoqin X Smith Nathan A NA Ziobro Julie J Curiel Julian J Tenga Milagros J MJ Martin Brandon B Freedman Samuel S Cea-Del Rio Christian A CA Oboti Livio L Tsuchida Tammy N TN Oluigbo Chima C Yaun Amanda A Magge Suresh N SN O'Neill Brent B Kao Amy A Zelleke Tesfaye G TG Depositario-Cabacar Dewi T DT Ghimbovschi Svetlana S Knoblach Susan S Ho Chen-Ying CY Corbin Joshua G JG Goodkin Howard P HP Vicini Stefano S Huntsman Molly M MM Gaillard William D WD Valdez Gregorio G Liu Judy S JS

Neuron 20171001 2

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<sup>flox/flox</sup> and PV-Cre; Clock<sup>flox/flox</sup> mouse lines with targeted deletions of the Clock gene in excitatory and parvalbumin (PV)- ...[more]

PMID: 29024662

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Project description:Normal brain functioning is presumed to depend upon interacting regions within large-scale neuronal networks. Increasing evidence exists that interictal network alterations in focal epilepsy are associated with cognitive and behavioral deficits. Nevertheless, the reported network alterations are inconclusive and prone to low statistical power due to small sample sizes as well as modest effect sizes. We therefore systematically reviewed the existing literature and conducted a meta-analysis to characterize the changes in whole-brain interictal focal epilepsy networks at sufficient power levels. We focused on the two most commonly used metrics in whole-brain networks: average path length and average clustering coefficient. Twelve studies were included that reported whole-brain network average path length and average clustering coefficient characteristics in patients and controls. The overall group difference, quantified as the standardized mean average path length difference between epilepsy and control groups, corresponded to a significantly increased average path length of 0.29 (95% confidence interval (CI): 0.12 to 0.45, p = 0.0007) in the epilepsy group. This suggests a less integrated interictal whole-brain network. Similarly, a significantly increased standardized mean average clustering coefficient of 0.35 (CI: 0.05 to 0.65, p = 0.02) was found in the epilepsy group in comparison with controls, pointing towards a more segregated interictal network. Sub-analyses revealed similar results for functional and structural networks in terms of effect size and directionality for both metrics. In addition, we found individual network studies to be prone to low power due to the relatively small group differences in average path length and average clustering coefficient in combination with small sample sizes. The pooled network characteristics support the hypothesis that focal epilepsy has widespread detrimental effects, that is, reduced integration and increased segregation, on whole brain interictal network organization, which may relate to the co-morbid cognitive and behavioral impairments often reported in patients with focal epilepsy.

Dataset Information

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

Publications

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

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