Epigenetic regulation of the circadian gene<i>Per1</i>in the hippocampus mediates age-related changes in memory and synaptic plasticity

Kwapis, Janine L.; Alaghband, Yasaman; Ea, Kramár; Aj, López; Av, Ciernia; Ao, White; G, Shu; Rhee, Diane; Cm, Michael; Montellier, Emilie; Y, Liu; Cn, Magnan; Sassone–Corsi, Paolo; Baldi, Pierre; Dp, Matheos; Ma, Wood

doi:10.1101/301135

Cited by 3 publications

(3 citation statements)

References 52 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar results were obtained in mice kept in constant darkness (Figures S1C and S1D). These results are consistent with previous studies in the hippocampus of 4-to 6-month-old mice and in hippocampal slice cultures and expand them, showing that the transcriptiontranslation feedback loops responsible for the circadian regulation of clock gene expression are functional also in the hippocampus of juvenile mice (Kwapis et al, 2018;Namihira et al, 1999;Wang et al, 2009).…”

Section: Resultssupporting

confidence: 93%

Circadian Modulation of Neurons and Astrocytes Controls Synaptic Plasticity in Hippocampal Area CA1

et al. 2020

View full text Add to dashboard Cite

SUMMARY Most animal species operate according to a 24-h period set by the suprachiasmatic nucleus (SCN) of the hypothalamus. The rhythmic activity of the SCN modulates hippocampal-dependent memory, but the molecular and cellular mechanisms that account for this effect remain largely unknown. Here, we identify cell-type-specific structural and functional changes that occur with circadian rhythmicity in neurons and astrocytes in hippocampal area CA1. Pyramidal neurons change the surface expression of NMDA receptors. Astrocytes change their proximity to synapses. Together, these phenomena alter glutamate clearance, receptor activation, and integration of temporally clustered excitatory synaptic inputs, ultimately shaping hippocampal-dependent learning in vivo . We identify corticosterone as a key contributor to changes in synaptic strength. These findings highlight important mechanisms through which neurons and astrocytes modify the molecular composition and structure of the synaptic environment, contribute to the local storage of information in the hippocampus, and alter the temporal dynamics of cognitive processing.

show abstract

Section: Resultssupporting

confidence: 93%

Circadian Modulation of Neurons and Astrocytes Controls Synaptic Plasticity in Hippocampal Area CA1

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Stably transfected cells were selected with puromycin (Sigma-Aldrich, St Louis, MO, USA). In addition, lentiviral vectors expressing human PER1 (Lv-PER1), P53 (Lv-P53), YTHDF2-specific shRNA (shYTHDF2), empty vectors (vector), and plasmids containing scrambled shRNA (scramble) were constructed as previously described [25][26][27].…”

Section: Vector Construction and Transductionmentioning

confidence: 99%

RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner

et al. 2020

View full text Add to dashboard Cite

Background N6-methyladenosine (m6A) is the most abundant reversible methylation modification of eukaryotic mRNA, and it plays vital roles in tumourigenesis. This study aimed to explore the role of the m6A demethylase ALKBH5 in pancreatic cancer (PC). Methods The expression of ALKBH5 and its clinicopathological impact were evaluated in PC cohorts. The effects of ALKBH5 on the biological characteristics of PC cells were investigated on the basis of gain-of-function and loss-of-function analyses. Subcutaneous and orthotopic models further uncovered the role of ALKBH5 in tumour growth. mRNA and m6A sequencing and assays of m6A methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the targeted effect of ALKBH5 on PER1. P53-binding sites in the ALKBH5 promoter were investigated by ChIP and luciferase assays to reveal the interplay between ALKBH5 and PER1-activated ATM-CHK2-P53/CDC25C signalling. Results ALKBH5 loss characterized the occurrence and poor clinicopathological manifestations in patients with PC. Overexpression of ALKBH5 reduced tumoural proliferative, migrative, invasive activities in vitro and ameliorated tumour growth in vivo, whereas ALKBH5 knockdown facilitated PC progression. Mechanistically, ALKBH5 posttranscriptionally activated PER1 by m6A demethylation in an m6A-YTHDF2-dependent manner. PER1 upregulation led to the reactivation of ATM-CHK2-P53/CDC25C signalling, which inhibited cell growth. P53-induced activation of ALKBH5 transcription acted as a feedback loop regulating the m6A modifications in PC. Conclusion ALKBH5 serves as a PC suppressor by regulating the posttranscriptional activation of PER1 through m6A abolishment, which may highlight a demethylation-based approach for PC diagnosis and therapy.

show abstract

“…Since RCAN1 is known to both inhibit and facilitate CaN function (Vega et al, 2003;Liu et al, 2009;Wong et al, 2015) and to act independently of CaN (Keating et al, 2008), future studies are needed to determine how CaN participates in RCAN1-mediated daily activity rhythm disruptions associated with DS, AD, and aging. Moreover, it will be informative to assess rhythmic changes in hippocampal CaN activity, considering that the hippocampus contains an autonomous molecular clock that has been linked to memory performance (Kondratova et al, 2010;Smarr et al, 2014;Kwapis et al, 2018), and since hippocampus-dependent memory de cits were previously observed in both Rcan1 KO (Hoeffer et al, 2007) and RCAN1 TG (Wong et al, 2015) mice. Furthermore, pro ling the rhythmicity of RCAN1 levels and RCAN1-dependent modulation of CaN activity in other brain regions, such as the SCN, will be essential to establish if RCAN1 differentially regulates rhythmicity throughout the brain and to delineate the mechanisms whereby RCAN1 regulates diurnal and circadian activity patterns and rhythms.…”

Section: Discussionmentioning

confidence: 99%

RCAN1 Knockout and Overexpression Recapitulate an Ensemble of Rest-activity and Circadian Disruptions Characteristic of Down Syndrome, Alzheimer’s Disease, and Normative Aging

Wong

Buck

Borski

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Regulator of calcineurin 1 (RCAN1) is overexpressed in Down syndrome (DS), but RCAN1 levels are also increased in Alzheimer's disease (AD) and normal aging. AD is highly comorbid among individuals with DS and is characterized in part by progressive neurodegeneration that resembles accelerated aging. Importantly, abnormal RCAN1 levels have been demonstrated to promote memory deficits and pathophysiology symptomatic of DS, AD, and aging. Anomalous diurnal rest-activity patterns and circadian rhythm disruptions are also common in DS, AD, and aging and have been implicated in facilitating age-related cognitive decline and AD progression. However, no prior studies have assessed whether RCAN1 dysregulation may also promote the age-associated alteration of rest-activity profiles and circadian rhythms, which could in turn contribute to neurodegeneration in DS, AD, and aging. Methods: The present study examined the impacts of RCAN1 deficiency and overexpression on the photic entrainment, circadian periodicity, intensity and distribution, diurnal patterning, and circadian rhythmicity of wheel running in young (3-6 months old) and aged (9-14 months old) mice. All data were initially analyzed by multifactorial ANOVA with variables of genotype, age, treatment, and sex considered as dependent variables.Results: We found that daily RCAN1 levels in the hippocampi of light-entrained young mice are generally constant and that balanced RCAN1 expression is necessary for normal circadian locomotor activity rhythms. While the light-entrained diurnal period was unaltered, RCAN1-null and -overexpressing mice displayed lengthened endogenous (free-running) circadian periods like mouse models of AD and aging. In light-entrained young mice, RCAN1 knockout and overexpression also recapitulated the general hypoactivity, diurnal rest-wake pattern fragmentation, and attenuated amplitudes of circadian activity rhythms reported in DS, preclinical and clinical AD, healthily aging individuals, and rodent models thereof. Under constant darkness, RCAN1-null and -overexpressing mice displayed altered locomotor behavior indicating circadian clock dysfunction. Using the Dp(16)1Yey/+ (Dp16) mouse model for DS, which expresses three copies of Rcan1, we found reduced wheel running activity and rhythmicity in both light-entrained and free-running young Dp16 mice like young RCAN1-overexpressing mice. Critically, these diurnal and circadian deficits were rescued in part or entirely by restoring Rcan1 to two copies in Dp16 mice. Conclusions: Collectively, this study's findings suggest that both loss and aberrant gain of RCAN1 precipitate anomalous light-entrained diurnal and circadian activity patterns emblematic of DS, AD, and aging.

show abstract

Epigenetic regulation of the circadian genePer1in the hippocampus mediates age-related changes in memory and synaptic plasticity

Cited by 3 publications

References 52 publications

Circadian Modulation of Neurons and Astrocytes Controls Synaptic Plasticity in Hippocampal Area CA1

Circadian Modulation of Neurons and Astrocytes Controls Synaptic Plasticity in Hippocampal Area CA1

RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner

RCAN1 Knockout and Overexpression Recapitulate an Ensemble of Rest-activity and Circadian Disruptions Characteristic of Down Syndrome, Alzheimer’s Disease, and Normative Aging

Contact Info

Product

Resources

About