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

Li, Peijun; Fu, Xiaoqin; Smith, Nathan A.; Ziobro, Julie; Curiel, Julian; Tenga, Milagros J.; Martin, Brandon S.; Freedman, Samuel; Rio, Christian A. Cea-Del; Oboti, Livio; Tsuchida, Tammy N.; Oluigbo, Chima; Yaun, Amanda L.; Magge, Suresh N.; O’Neill, Brent R; Kao, Amy H.; Zelleke, Tesfaye; Depositario-Cabacar, Dewi; Ghimbovschi, Svetlana; Knoblach, Susan M.; Ho, Chen-Ying; Corbin, Joshua G.; Goodkin, Howard P.; Vicini, Stefano; Huntsman, Molly M.; Gaillard, William D.; Valdez, Gregorio; Liu, Judy S.

doi:10.1016/j.neuron.2017.09.044

Cited by 70 publications

(81 citation statements)

References 55 publications

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“…In another study, the deletion of Hlf in mouse exacerbated seizures and reduced survival in the Snc2a Q54 mouse model of epilepsy 55 . Likewise, DBP was found downregulated together with CLOCK, CRY1 and PER1 at protein levels in patients with focal cortical dysplasia 3 . Furthermore, neuroprotective effects were described for E4bp4, which we found here to be upregulated after induction of status epilepticus.…”

Section: Discussionmentioning

confidence: 93%

“…Even though the occurrence of epileptic seizures in circadian patterns has been documented in animal models as well as humans 53 the relationship between epileptic seizures and the circadian system at the molecular level is still unclear. A recent study reported decreased Clock expression in human epileptogenic tissue and decreased seizure www.nature.com/scientificreports www.nature.com/scientificreports/ threshold in mice with Clock deletion in excitatory cortical neurons suggesting that alterations in Clock expression are epileptogenic 3 . Furthermore, mice deficient for Bmal1 exhibited reduced seizure thresholds 13 .…”

Section: Discussionmentioning

confidence: 99%

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Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

Rambousek

Gschwind

Lafourcade

et al. 2020

Sci Rep

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epilepsy is a widespread neurological disease characterized by abnormal neuronal activity resulting in recurrent seizures. there is mounting evidence that a circadian system disruption, involving clock genes and their downstream transcriptional regulators, is associated with epilepsy. in this study, we characterized the hippocampal expression of clock genes and pAR bZip transcription factors (tfs) in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainic acid (KA). the expression of PAR bZIP TFs was significantly altered following KA injection as well as in other rodent models of acquired epilepsy. Although the PAR bZIP TFs are regulated by proinflammatory cytokines in peripheral tissues, we discovered that the regulation of their expression is inflammation-independent in hippocampal tissue and rather mediated by clock genes and hyperexcitability. furthermore, we report that hepatic leukemia factor (Hlf), a member of pAR bZip tfs family, is invariably downregulated in animal models of acquired epilepsy, regulates neuronal activity in vitro and its overexpression in dentate gyrus neurons in vivo leads to altered expression of genes associated with seizures and epilepsy. overall, our study provides further evidence of pAR bZip tfs involvement in epileptogenesis and points to Hlf as the key player. Epilepsy is a chronic brain disease characterized by the occurrence of recurrent seizures, which are the result of an excessive electrical discharge or hypersynchronization of a group of neurons in distinct areas of the brain. Temporal lobe epilepsy (TLE) is the most common subtype of acquired epilepsy 1. TLE, affecting the hippocampal formation and surrounding cortices of the temporal lobe, is associated with pathological changes including neuroinflammation and neurodegeneration resulting in impaired cognition 2. Recent studies provided converging evidence that the circadian system might be disrupted in epilepsy 3,4. At the molecular level, core clock genes form a transcriptional-translational feedback loop that drives their diurnal oscillations. The positive loop members CLOCK (or NPAS2) and BMAL1 form heterodimers that activate the expression of negative feedback loop members, CRY and PER, by binding to E-box motives in their promoters. CRY and PER consequently inhibit the transcriptional activity of CLOCK/NPAS2:BMAL1 complex and thereby their own expression. The inhibition of BMAL1 expression is additionally mediated in a second negative feedback loop by REV-erb-α and RORC 5,6. Moreover, core clock components interact with the expression of the proline and acidic amino acid-rich basic leucine zipper (PAR bZIP) transcription factors (TFs). This family is composed of three activators, DBP (albumin D-site-binding protein), HLF (hepatic leukemia factor), TEF (thyrotrophic embryonic factor) and one suppressor of transcription E4 Promoter-Binding Protein 4 (E4BP4), known also as NFIL3 7-10. It has been shown that E4BP4 has an opposite rhythm of oscillation compared to positive members of PAR...

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

Rambousek

Gschwind

Lafourcade

et al. 2020

Sci Rep

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“…Interestingly, transcriptome analysis revealed that Clk expression is reduced in human epileptogenic tissue, and a reduction in Clk expression contributes to malformation of the dendritic spine. These data suggest that CLK transcriptional activity is required for neuronal structural integrity (Li et al, 2017).…”

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confidence: 76%

AMP-activated protein kinase regulates circadian rhythm by affecting CLOCK in Drosophila

et al. 2019

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The circadian clock organizes the physiology and behavior of organisms to their daily environmental rhythms. The central circadian timekeeping mechanism in eukaryotic cells is the transcriptional-translational feedback loop (TTFL). In the Drosophila TTFL, the transcription factors CLOCK (CLK) and CYCLE (CYC) play crucial roles in activating expression of core clock genes and clock-controlled genes. Many signaling pathways converge on the CLK/CYC complex and regulate its activity to fine-tune the cellular oscillator to environmental time cues. We aimed to identify factors that regulate CLK by performing tandem affinity purification combined with mass spectrometry using Drosophila S2 cells that stably express HA/FLAG-tagged CLK and V5-tagged CYC. We identified SNF4A␥, a homolog of mammalian AMP-activated protein kinase ␥ (AMPK␥), as a factor that copurified with HA/FLAG-tagged CLK. The AMPK holoenzyme composed of a catalytic subunit AMPK␣ and two regulatory subunits, AMPK␤ and AMPK␥, directly phosphorylated purified CLK in vitro. Locomotor behavior analysis in Drosophila revealed that knockdown of each AMPK subunit in pacemaker neurons induced arrhythmicity and long periods. Knockdown of AMPK␤ reduced CLK levels in pacemaker neurons, and thereby reduced pre-mRNA and protein levels of CLK downstream core clock genes, such as period and vrille. Finally, overexpression of CLK reversed the long-period phenotype that resulted from AMPK␤ knockdown. Thus, we conclude that AMPK, a central regulator of cellular energy metabolism, regulates the Drosophila circadian clock by stabilizing CLK and activating CLK/CYC-dependent transcription. Hardin (Texas A&M) for generously providing anti-CLK and anti-VRI antibodies; Thomas Kusch (Rutgers University) for providing the pMT-HA/FLAG plasmid; and Joungkyeong Chung (Seoul National University) for providing the AMPK null mutants.Regulation of the circadian transcription factors CLK and CYC is fundamental to synchronize the core clock with environmental changes. Here, we show that the AMPK␥ subunit of AMPK, a central regulator of cellular metabolism, copurifies with the CLK/CYC complex in Drosophila S2 cells. Furthermore, the AMPK holoenzyme directly phosphorylates CLK in vitro. This study demonstrates that AMPK activity regulates the core clock in Drosophila by activating CLK, which enhances circadian transcription. In mammals, AMPK affects the core clock by downregulating circadian repressor proteins. It is intriguing to note that AMPK activity is required for core clock regulation through circadian transcription enhancement, whereas the target of AMPK action is different in Drosophila and mammals (positive vs negative element, respectively).

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“…This phenomenon appears to be mediated, in part, by genetic factors that suggest a circadian influence. For example, neuronal excitability in epileptic mice and human epileptic brain tissue has implicated the CLOCK‐BMAL1 circadian protein complex in the diurnal variation of the seizure threshold . Circadian cycles have been observed in seizures, as well as diurnal variation in seizure clusters and status epilepticus .…”

Section: Introductionmentioning

confidence: 99%

“…For example, neuronal excitability in epileptic mice and human epileptic brain tissue has implicated the CLOCK-BMAL1 circadian protein complex in the diurnal variation of the seizure threshold. 15,16 Circadian cycles have been observed in seizures, 17,18 as well as diurnal variation in seizure clusters and status epilepticus. 19 Therefore, abrupt circadian shifts (eg, with DST or travel), with or without concomitant sleep deprivation, may predispose to increased seizure frequency as well.…”

Section: Introductionmentioning

confidence: 99%

Daylight saving time transitions are not associated with increased seizure incidence

Schneider

Moss²,

Goldenholz

2019

Epilepsia

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Summary Objective Given the known association of daylight saving time (DST) transitions with increased risk of accidents, heart attack, and stroke, we aimed to determine whether seizures, which are reportedly influenced by sleep and circadian disruption, also increased in frequency following the transition into DST. Methods Using Seizure Tracker's self‐reported data from 12 401 individuals from 2008‐2016, 932 717 seizures were assessed for changes in incidence in relation to DST transitions. Two methods of standardization—z scores and unit‐scaled rate ratios (RRs)—were used to compare seizure propensities following DST transitions to other time periods. Results As a percentile relative to all other weeks in a given year, absolute seizure counts in the week of DST fell below the median (DST seizure percentiles mean ± SD: 19.68 ± 16.25, P = 0.01), which was concordant with weekday‐specific comparisons. Comparatively, RRs for whole‐week (1.06, 95% confidence interval [CI] 1.02‐1.10, P = 0.0054) and weekday‐to‐weekday (RR range 1.04‐1.16, all P < 0.001) comparisons suggested a slightly higher incidence of seizures in the DST week compared to all other weeks of the year. However, examining the similar risk of the week preceding and following the DST‐transition week revealed no significant weekday‐to‐weekday differences in seizure incidence, although there was an unexpected, modestly decreased seizure propensity in the DST week relative to the whole week prior (RR 0.94, 95% CI 0.91‐0.96, P < 0.001). Significance Despite expectations that circadian and sleep disruption related to DST transitions would increase the incidence of seizures, we found little substantive evidence for such an association in this large, longitudinal cohort. Although large‐scale observational/epidemiologic cohorts can be effective at answering such questions, additional covariates (eg, sleep duration, seizure type, and so on) that may underpin the association were not able available, so the association has not definitively been ruled out.

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

Cited by 70 publications

References 55 publications

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

AMP-activated protein kinase regulates circadian rhythm by affecting CLOCK in Drosophila

Daylight saving time transitions are not associated with increased seizure incidence

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