Isabelle Schmutz

Université de Fribourg, Freiburg, Fribourg, Switzerland

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Publications (16)61.54 Total impact

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    ABSTRACT: Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting have been shown to be largely dependent on both membrane depolarization and intracellular second-messenger signaling. In both of these processes, voltage-gated calcium channels (VGCCs) mediate voltage-dependent calcium influx, which propagates neural impulses by stimulating vesicle fusion and instigates intracellular pathways resulting in clock gene expression. Through the cumulative actions of these processes, the phase of the internal clock is modified to match the light cycle of the external environment. To parse out the distinct roles of the L-type VGCCs, we analyzed mice deficient in Cav1.2 (Cacna1c) in brain tissue. We found that mice deficient in the Cav1.2 channel exhibited a significant reduction in their ability to phase-advance circadian behavior when subjected to a light pulse in the late night. Furthermore, the study revealed that the expression of Cav1.2 mRNA was rhythmic (peaking during the late night) and was regulated by the circadian clock component REV-ERBα. Finally, the induction of clock genes in both the early and late subjective night was affected by the loss of Cav1.2, with reductions in Per2 and Per1 in the early and late night, respectively. In sum, these results reveal a role of the L-type VGCC Cav1.2 in mediating both clock gene expression and phase advances in response to a light pulse in the late night.
    Journal of Biological Rhythms 08/2014; 29(4):288-98. · 3.23 Impact Factor
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    ABSTRACT: The function of the nuclear receptor Rev-erbα (Nr1d1) in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO) animals. We identified fatty acid binding protein 7 (Fabp7, Blbp) as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ) of the hippocampus, where neuronal progenitor cells (NPCs) can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer.
    PLoS ONE 01/2014; 9(6):e99883. · 3.53 Impact Factor
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    Dataset: Carvas2012
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    ABSTRACT: Period2 (Per2) is an important component of the circadian clock. Mutation of this gene is associated with vascular endothelial dysfunction and altered glucose metabolism. The aim of this study is to further characterize whole body glucose homeostasis and endothelial nitric oxide (NO) production in response to insulin in the mPer2(Brdm1) mice. We show that mPer2(Brdm1) mice exhibit compromised insulin receptor activation and Akt signaling in various tissues including liver, fat, heart, and aortas with a tissue-specific heterogeneous diurnal pattern, and decreased insulin-stimulated NO release in the aortas in both active and inactive phases of the animals. As compared to wild type (WT) mice, the mPer2(Brdm1) mice reveal hyperinsulinemia, hypoglycemia with lower fasting hepatic glycogen content and glycogen synthase level, no difference in glucose tolerance and insulin tolerance. The mPer2(Brdm1) mice do not show increased predisposition to obesity either on normal chow or high fat diet compared to WT controls. Thus, mice with Per2 gene mutation show altered glucose homeostasis and compromised insulin-stimulated NO release, independently of obesity.
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    ABSTRACT: Period2 (Per2) is an important component of the circadian clock. Mutation of this gene is associated with vascular endothelial dysfunction and altered glucose metabolism. The aim of this study is to further characterize whole body glucose homeostasis and endothelial nitric oxide (NO) production in response to insulin in the mPer2(Brdm1) mice. We show that mPer2(Brdm1) mice exhibit compromised insulin receptor activation and Akt signaling in various tissues including liver, fat, heart, and aortas with a tissue-specific heterogeneous diurnal pattern, and decreased insulin-stimulated NO release in the aortas in both active and inactive phases of the animals. As compared to wild type (WT) mice, the mPer2(Brdm1) mice reveal hyperinsulinemia, hypoglycemia with lower fasting hepatic glycogen content and glycogen synthase level, no difference in glucose tolerance and insulin tolerance. The mPer2(Brdm1) mice do not show increased predisposition to obesity either on normal chow or high fat diet compared to WT controls. Thus, mice with Per2 gene mutation show altered glucose homeostasis and compromised insulin-stimulated NO release, independently of obesity.
    Frontiers in Physiology 01/2012; 3:337.
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    ABSTRACT: The liver is the important organ to maintain energy homeostasis of an organism. To achieve this, many biochemical reactions run in this organ in a rhythmic fashion. An elegant way to coordinate the temporal expression of genes for metabolic enzymes relies in the link to the circadian timing system. In this fashion not only a maximum of synchronization is achieved, but also anticipation of daily recurring events is possible. Here we will focus on the input and output pathways of the hepatic circadian oscillator and discuss the recently found flexibility of its circadian transcriptional networks.
    Molecular and Cellular Endocrinology 06/2011; 349(1):38-44. · 4.04 Impact Factor
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    ABSTRACT: Daily patterns of animal behavior are potentially of vast functional importance. Fitness benefits have been identified in nature by the association between individual timing and survival or by the fate of individuals after experimental deletion of their circadian pacemaker. The recent advances in unraveling the molecular basis of circadian timing enable new approaches to natural selection on timing. The investigators report on the effect and fate of the mutant Per2(Brdm1) allele in 4 replicate populations of house mice in a seminatural outside environment over 2 years. This allele is known to compromise circadian organization and entrainment and to cause multiple physiological disturbances. Mice (N=250) bred from Per2(Brdm1) heterozygotes were implanted subcutaneously with transponders and released in approximately Mendelian ratios in four 400 m(2) pens. An electronic system stored the times of all visits to feeders of each individual. The study first demonstrates that mice are not explicitly nocturnal in this natural environment. Feeding activity was predominantly and sometimes exclusively diurnal and spread nearly equally over day and night under the protective snow cover in winter. The effect of Per2(Brdm1) on activity timing is negligible compared to seasonal changes in all genotypes. Second, the Per2(Brdm1) allele did not have persistent negative effects on fitness. In the first year, the allele gradually became less frequent by reducing survival. New cohorts captured had the same Per2(Brdm1) frequency as the survivors from previous cohorts, consistent with an absence of an effect on reproduction. In the second year, the allele recovered to about its initial frequency (0.54). These changes in selective advantage were primarily due to female mice, as females lived longer and the sex ratio dropped to about 25% males in the population. While it is unknown which selective advantage led to the recovery, the results caution against inferences from laboratory experiments on fitness consequences in the natural environment. It also demonstrates that the activity of mice, while strictly nocturnal in the laboratory, may be partially or completely diurnal in the field. The new method allows assessment of natural selection on specific alleles on a day-today basis.
    Journal of Biological Rhythms 04/2011; 26(2):118-29. · 3.23 Impact Factor
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    ABSTRACT: Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock.
    PLoS ONE 01/2011; 6(6):e21325. · 3.53 Impact Factor
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    Jürgen A Ripperger, Isabelle Schmutz, Urs Albrecht
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    ABSTRACT: The recurring light/dark cycle that has a period length of about 24 hours has been internalized in various organisms in the form of a circadian clock. This clock allows a precise orchestration of biochemical and physiological processes in the body thus improving performance. Recently, we found that the clock component PERIOD2 (PER2) can coordinate transcriptional regulation of metabolic, physiological, or behavioral pathways by interacting with nuclear receptors. PER2 appears to act as co-regulator of nuclear receptors linking clock function and transcriptional regulation at the level of protein-protein interactions. Here, we provide additional evidence for modulation of nuclear receptor dependent transcription by PER2 underscoring the broad implication of our finding. Taken together, our findings provide a base for the understanding of various disorders including mood disorders that have their roots in a temporal deregulation of basic metabolic processes.
    Cell cycle (Georgetown, Tex.) 07/2010; 9(13):2515-21. · 5.24 Impact Factor
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    ABSTRACT: Mammalian circadian clocks provide a temporal framework to synchronize biological functions. To obtain robust rhythms with a periodicity of about a day, these clocks use molecular oscillators consisting of two interlocked feedback loops. The core loop generates rhythms by transcriptional repression via the Period (PER) and Cryptochrome (CRY) proteins, whereas the stabilizing loop establishes roughly antiphasic rhythms via nuclear receptors. Nuclear receptors also govern many pathways that affect metabolism and physiology. Here we show that the core loop component PER2 can coordinate circadian output with the circadian oscillator. PER2 interacts with nuclear receptors including PPARalpha and REV-ERBalpha and serves as a coregulator of nuclear receptor-mediated transcription. Consequently, PER2 is rhythmically bound at the promoters of nuclear receptor target genes in vivo. In this way, the circadian oscillator can modulate the expression of nuclear receptor target genes like Bmal1, Hnf1alpha, and Glucose-6-phosphatase. The concept that PER2 may propagate clock information to metabolic pathways via nuclear receptors adds an important facet to the clock-dependent regulation of biological networks.
    Genes & development 02/2010; 24(4):345-57. · 12.08 Impact Factor
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    ABSTRACT: A strong stimulus adjusting the circadian clock to the prevailing light-dark cycle is light. However, the circadian clock is reset by light only at specific times of the day. The mechanisms mediating such gating of light input to the CNS are not well understood. There is evidence that Ca(2+) ions play an important role in intracellular signaling mechanisms, including signaling cascades stimulated by light. Therefore, Ca(2+) is hypothesized to play a role in the light-mediated resetting of the circadian clock. Calbindin-D28k (CB; gene symbol: Calb1) is a Ca(2+) binding protein implicated in Ca(2+) homeostasis and sensing. The absence of this protein influences Ca(2+) buffering capacity of a cell, alters spatio-temporal aspects of intracellular Ca(2+) signaling, and hence might alter transmission of light information to the circadian clock in neurons of the suprachiasmatic nuclei (SCN). We tested mice lacking a functional Calb1 gene (Calb1(-/-)) and found an increased phase-delay response to light applied at circadian time (CT) 14 in these animals. This is accompanied by elevated induction of Per2 gene expression in the SCN. Period length and circadian rhythmicity were comparable between Calb1(-/-) and wild-type animals. Our findings indicate an involvement of CB in the signaling pathway that modulates the behavioral and molecular response to light.
    Chronobiology International 01/2010; 27(1):68-82. · 4.35 Impact Factor
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    ABSTRACT: Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype. We found that Per2(Brdm1) mutant mice as well as mice lacking Cry2(-/-) displayed significantly increased bone volume at 12 weeks of age, when bone turnover is high. Per2(Brdm1) mutant mice showed alterations in parameters specific for osteoblasts whereas mice lacking Cry2(-/-) displayed changes in osteoclast specific parameters. Interestingly, inactivation of both Per2 and Cry2 genes leads to normal bone volume as observed in wild type animals. Importantly, osteoclast parameters affected due to the lack of Cry2, remained at the level seen in the Cry2(-/-) mutants despite the simultaneous inactivation of Per2. This indicates that Cry2 and Per2 affect distinct pathways in the regulation of bone volume with Cry2 influencing mostly the osteoclastic cellular component of bone and Per2 acting on osteoblast parameters.
    PLoS ONE 01/2010; 5(7):e11527. · 3.53 Impact Factor
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    ABSTRACT: Neurotransmitters are concentrated into synaptic vesicles by VGLUT (vesicular glutamate transporter) or VGAT (vesicular GABA transporter). The number of VGLUTs per vesicle determines the amount of stored neurotransmitter, thereby influencing postsynaptic response. Recently, we described a strong diurnal cycling of the amount of VGLUT1 on synaptic vesicles prepared from whole mouse brain at different times of the day (Yelamanchili, S. V., Pendyala, G., Brunk, I., Darna, M., Albrecht, U., and Ahnert-Hilger, G. (2006) J. Biol. Chem. 281, 15671-15679). To analyze whether and how much VGLUT resides in cellular versus vesicular membranes, we developed a Pronase assay. We found that VGLUT and synaptotagmin are highly accessible to proteolytic cleavage in rat and mouse synaptosomal preparations, indicating considerable amounts of these vesicular proteins at the plasma membrane, whereas only minor amounts of synaptophysin and Rab3 are digested. Sucrose stimulation increases digestion of VGLUT, synaptotagmin, and synaptophysin due to membrane fusion that exposes the lumen-facing peptides to the extracellular space. Digestion of mouse synaptosomes prepared at different times of the day revealed a diurnal cycling of VGLUT to the plasma membrane. More VGLUT is digested at noon (Zeitgeber time 6) compared with the start of the light period (Zeitgeber time 0), whereas digestion of synaptophysin and synaptotagmin is independent of diurnal cycling. In contrast to VGLUT, the amount of VGAT appears not to vary diurnally but is decreased in membrane preparations from animals kept under constant darkness. We conclude that VGLUTs are sorted diurnally to the plasma membrane to modulate glutamate transmission during a day/night cycle, whereas VGAT expression is not oscillating but is increased in the presence of a light/dark cycle.
    Journal of Biological Chemistry 01/2009; 284(7):4300-7. · 4.65 Impact Factor
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    ABSTRACT: The circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3-5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6-10]. To establish a molecular link between the circadian-clock mechanism and dopamine metabolism, we analyzed the murine promoters of genes encoding key enzymes important in dopamine metabolism. We find that transcription of the monoamine oxidase A (Maoa) promoter is regulated by the clock components BMAL1, NPAS2, and PER2. A mutation in the clock gene Per2 in mice leads to reduced expression and activity of MAOA in the mesolimbic dopaminergic system. Furthermore, we observe increased levels of dopamine and altered neuronal activity in the striatum, and these results probably lead to behavioral alterations observed in Per2 mutant mice in despair-based tests. These findings suggest a role of circadian-clock components in dopamine metabolism highlighting a role of the clock in regulating mood-related behaviors.
    Current Biology 06/2008; 18(9):678-83. · 9.49 Impact Factor
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    ABSTRACT: We investigated the role of the two calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB) in the locomotor activity and motor coordination using null-mutant mice for PV (PV-/-), CB (CB-/-) or both proteins (PV-/-CB-/-). These proteins are expressed in distinct, mainly non-overlapping populations of neurons of the central and peripheral nervous system and PV additionally in fast-twitch muscles. In a test measuring repeated locomotor activity during 18-20 days, the analysis revealed a slightly increased activity in mice lacking either protein, while the lack of both decreased the number of beams crossed during active periods. An increase in the characteristic speed during the first 8 days could be attributed to PV-deficiency, while the elimination of CB in CB-/- and double-KO mice decreased the percentage of fast movements at all time points. In the latter, additionally a reduction of the fastest speed was observed. The alterations in locomotor activity (fast movements, fastest speed) strongly correlate with the impairment in locomotor coordination in mice deficient for CB evidenced in the runway assay and the rotarod assay. The graded locomotor phenotype (CB>PV) is qualitatively correlated with alterations in Purkinje cell firing reported previously in these mice. The presence or absence of either protein did not affect the spontaneous locomotor activity when animals were placed in a novel environment and tested only once for 30 min. In summary, the lack of these calcium-binding proteins yields characteristic, yet distinct phenotypes with respect to locomotor activity and coordination.
    Behavioural Brain Research 03/2007; 178(2):250-61. · 3.33 Impact Factor
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    ABSTRACT: The Period 2 (Per2) gene is an important component of the circadian system. It appears to be not only part of the core oscillator mechanism, but also part of the input and output pathways of the clock. Because of its involvement at multiple levels of the circadian system, Per2 needs to meet a variety of different demands. We discuss how Per2 might be able to fulfill multiple functions by reviewing known facts and combine this with speculations based on these facts. This might provide new views about Per2 function and help to better understand diseases that are rooted in the circadian system.
    Cold Spring Harbor Symposia on Quantitative Biology 02/2007; 72:95-104.
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    ABSTRACT: Most behavioral experiments within circadian research are based on the analysis of locomotor activity. This paper introduces scientists to chronobiology by explaining the basic terminology used within the field. Furthermore, it aims to assist in designing, carrying out, and evaluating wheel-running experiments with rodents, particularly mice. Since light is an easily applicable stimulus that provokes strong effects on clock phase, the paper focuses on the application of different lighting conditions.
    Biological Procedures Online 02/2005; 7:101-16. · 1.30 Impact Factor