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Savioz A.,University of Geneva | Leuba G.,Center for Psychiatric Neuroscience | Vallet P.G.,University of Geneva
Ageing Research Reviews | Year: 2015

The postsynaptic density protein PSD-95 is a major element of synapses. PSD-95 is involved in aging, Alzheimer's disease (AD) and numerous psychiatric disorders. However, contradictory data about PSD-95 expression in aging and AD have been reported. Indeed in AD versus control brains PSD-95 varies according to regions, increasing in the frontal cortex, at least in a primary stage, and decreasing in the temporal cortex. In contrast, in transgenic mouse models of aging and AD PSD-95 expression is decreased, in behaviorally aged impaired versus unimpaired rodents it can decrease or increase and finally, it is increased in rodents grown in enriched environments. Different factors explain these contradictory results in both animals and humans, among others concomitant psychiatric endophenotypes, such as depression. The possible involvement of PSD-95 in reactive and/or compensatory mechanisms during AD progression is underscored, at least before the occurrence of important synaptic elimination. Thus, in AD but not in AD transgenic mice, enhanced expression might precede the diminution commonly observed in advanced aging. A two-compartments cell model, separating events taking place in cell bodies and synapses, is presented. Overall these data suggest that AD research will progress by untangling pathological from protective events, a prerequisite for effective therapeutic strategies. © 2014 Elsevier B.V.

Jourdain P.,Ecole Polytechnique Federale de Lausanne | Becq F.,University of Poitiers | Lengacher S.,Ecole Polytechnique Federale de Lausanne | Boinot C.,University of Poitiers | And 4 more authors.
Journal of Cell Science | Year: 2014

The transmembrane water movements during cellular processes and their relationship to ionic channel activity remain largely unknown. As an example, in epithelial cells it was proposed that the movement of water could be directly linked to cystic fibrosis transmembrane conductance regulator (CFTR) protein activity through a cAMP-stimulated aqueous pore, or be dependent on aquaporin. Here, we used digital holographic microscopy (DHM) an interferometric technique to quantify in situ the transmembrane water fluxes during the activity of the epithelial chloride channel, CFTR, measured by patch-clamp and iodide efflux techniques. We showed that the water transport measured by DHM is fully inhibited by the selective CFTR blocker CFTRinh172 and is absent in cells lacking CFTR. Of note, in cells expressing the mutated version of CFTR (F508del-CFTR), which mimics the most common genetic alteration encountered in cystic fibrosis, we also show that the water movement is profoundly altered but restored by pharmacological manipulation of F508del-CFTRdefective trafficking. Importantly, whereas activation of this endogenous water channel required a cAMP-dependent stimulation of CFTR, activation of CFTR or F508del-CFTR by two cAMP-independent CFTR activators, genistein and MPB91, failed to trigger water movements. Finally, using a specific smallinterfering RNA against the endogenous aquaporin AQP3, the water transport accompanying CFTR activity decreased. We conclude that water fluxes accompanying CFTR activity are linked to AQP3 but not to a cAMP-stimulated aqueous pore in the CFTR protein. © 2014. Published by The Company of Biologists Ltd.

Finsterwald C.,Ecole Polytechnique Federale de Lausanne | Magistretti P.J.,Ecole Polytechnique Federale de Lausanne | Magistretti P.J.,Sudan University of Science and Technology | Magistretti P.J.,Center for Psychiatric Neuroscience | And 2 more authors.
Current Pharmaceutical Design | Year: 2015

The causes of neurodegenerative disorders are multiple, and for most of them a mechanistic understanding is still lacking. However, neurodegenerative diseases such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) all share common features that include elevated oxidative stress levels and impaired energy metabolism in the nervous system. Most of the current treatments are only successful at alleviating some of the pathological symptoms, but fail at preventing neurodegeneration. There is therefore an urgent need for innovative and more efficient treatments for neurodegenerative disorders. We review here the central role played by astrocytes in the regulation of brain homeostasis, protection and function by supporting neuronal health and activity. In particular, astrocytes are key partners of neuronal metabolism, notably through activation of the astrocyteneuron lactate shuttle (ANLS). They also control the levels of extracellular glutamate, production of antioxidant molecules, disposal of neuronal waste products, storage of energy in the form of glycogen, and expression of neurotrophic factors. These mechanisms, which are key for brain activity and cognition, also largely contribute to neuronal degeneration in pathological situations. Thus, as astrocytes appear to play a key role in the etiology of neurodegenerative disorders, a growing interest has arisen for astrocytemediated pathways as targets for drugs that aim at treating the root causes of the pathology. We present here the most recent and promising astrocyte-based therapeutic approaches - from fundamental discoveries to clinical trials - that intent to sustain neuronal health and function in neurodegenerative disorders. © 2015 Bentham Science Publishers.

Petit J.-M.,Ecole Polytechnique Federale de Lausanne | Petit J.-M.,Center for Psychiatric Neuroscience | Gyger J.,Ecole Polytechnique Federale de Lausanne | Burlet-Godinot S.,Ecole Polytechnique Federale de Lausanne | And 5 more authors.
Sleep | Year: 2013

Study Objectives: There is growing evidence indicating that in order to meet the neuronal energy demands, astrocytes provide lactate as an energy substrate for neurons through a mechanism called "astrocyte-neuron lactate shuttle" (ANLS). Since neuronal activity changes dramatically during vigilance states, we hypothesized that the ANLS may be regulated during the sleep-wake cycle. To test this hypothesis we investigated the expression of genes associated with the ANLS specifcally in astrocytes following sleep deprivation. Astrocytes were purifed by fuorescence-activated cell sorting from transgenic mice expressing the green fuorescent protein (GFP) under the control of the human astrocytic GFAP-promoter. Design: 6-hour instrumental sleep deprivation (TSD). Setting: Animal sleep research laboratory. Participants: Young (P23-P27) FVB/N-Tg (GFAP-GFP) 14Mes/J (Tg) mice of both sexes and 7-8 week male Tg and FVB/Nj mice. Interventions: Basal sleep recordings and sleep deprivation achieved using a modifed cage where animals were gently forced to move. Measurements and Results: Since Tg and FVB/Nj mice displayed a similar sleep-wake pattern, we performed a TSD in young Tg mice. Total RNA was extracted from the GFP-positive and GFP-negative cells sorted from cerebral cortex. Quantitative RT-PCR analysis showed that levels of Glut1, a-2-Na/K pump, Glt1, and Ldha mRNAs were signifcantly increased following TSD in GFP-positive cells. In GFP-negative cells, a tendency to increase, although not signifcant, was observed for Ldha, Mct2, and α-3-Na/K pump mRNAs. Conclusions: This study shows that TSD induces the expression of genes associated with ANLS specifcally in astrocytes, underlying the important role of astrocytes in the maintenance of the neuro-metabolic coupling across the sleep-wake cycle.

Garey L.,Center for Psychiatric Neuroscience
Journal of Anatomy | Year: 2010

Schizophrenia probably has a developmental origin. This review refers to three of our published series of studies related to this hypothesis: loss of dendritic spines on cerebral neocortical pyramidal neurons, decreased numerical density of glutamatergic neurons, and microgliosis. First, brains of schizophrenic patients and non-schizophrenic controls were obtained post mortem and blocks of multiple cortical areas impregnated with a Rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons of which the soma was in layer III (which takes part in corticocortical connectivity) and which met strict criteria for impregnation quality. Data were obtained blind: diagnoses were only revealed by a third party after measurements were completed. The mean spine count in all cortical areas studied in the control series was 243 mm-1 of dendrite and in the schizophrenics 108. Measurements in frontal and temporal association cortex showed the greatest reduction in spine number in schizophrenia (299 in control frontal cortex and 101 in schizophrenics, and 276 mm-1 in control temporal cortex and 125 in schizophrenics). There was no correlation of spine loss with age at death. Our results support the concept of a neurodevelopmental defect in the neuropil affecting glutamatergic neurons in schizophrenia and may help to explain loss of cortical volume without loss of neurons. In a second part of our study we used an antibody to the kainate receptor subunit GluR 5/6/7 and showed a decrease in numerical density of presumed glutamatergic neurons in schizophrenic orbitofrontal cortex. Finally, as glia play a major role in the developing nervous system, we investigated whether schizophrenia was associated with glial changes in frontal and temporal cortex. Astroglia and microglia were identified in schizophrenic and control brains, using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR), respectively. Significant increases were found in microglial numerical density in schizophrenics compared with controls: 28% in frontal area 9 (115 cells mm-2 compared with 89), and a 57% increase in temporal area 22 (139 cells mm-2 compared with 88). For both areas, astroglia showed no significant differences between schizophrenics and controls. No significant differences were found in cortical thickness or total neuronal numerical density between the two groups. This specific increase in numerical density of microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, could be related to possible changes in cortical neuropil architecture as revealed by loss of dendritic spines. © 2010 The Author. Journal of Anatomy © 2010 Anatomical Society of Great Britain and Ireland.

Magistretti P.J.,Ecole Polytechnique Federale de Lausanne | Magistretti P.J.,Center for Psychiatric Neuroscience
Cell Metabolism | Year: 2014

Functional brain imaging studies show that in certain brain regions glucose utilization exceeds oxygen consumption, indicating the predominance of aerobic glycolysis. In this issue, Goyal et al. (2014) report that this metabolic profile is associated with an enrichment in the expression of genes involved in synaptic plasticity and remodeling processes. © 2014 Elsevier Inc.

Boutrel B.,Center for Psychiatric Neuroscience | Cannella N.,Stanford University | de Lecea L.,Stanford University
Brain Research | Year: 2010

The hypocretins (Hcrts), also called orexins, are two neuropeptides secreted by a few thousand neurons restricted to the lateral hypothalamus. The Hcrt peptides bind to two receptors located in nuclei associated with diverse cognitive and physiological functions. Experimental evidence has demonstrated that the physiological roles of hypocretins extend far beyond its initial role in food consumption and has emerged as a key system in the fields of sleep disorders and drug addiction. Here, we discuss recent evidence demonstrating a key role of hypocretin in the motivation for reward seeking in general, and drug taking in particular, and we delineate a physiological framework for this peptidergic system in orchestrating the appropriate levels of alertness required for the elaboration and the execution of goal-oriented behaviors. We propose a general role for hypocretins in mediating arousal, especially when an organism must respond to unexpected stressors and environmental challenges, which serve to shape survival behaviors. We also discuss the limit of the current experimental paradigms to address the question of how a system normally involved in the regulation of vigilance states and hyperarousal may promote a pathological state that elicits compulsive craving and relapse to drug seeking. © 2009.

Finsterwald C.,Center for Psychiatric Neuroscience | Carrard A.,Center for Psychiatric Neuroscience | Martin J.-L.,Center for Psychiatric Neuroscience
PLoS ONE | Year: 2013

Substantial evidence supports a role for myocyte enhancer factor 2 (MEF2)-mediated transcription in neuronal survival, differentiation and synaptic function. In developing neurons, it has been shown that MEF2-dependent transcription is regulated by neurotrophins. Despite these observations, little is known about the cellular mechanisms by which neurotrophins activate MEF2 transcriptional activity. In this study, we examined the role of salt-inducible kinase 1 (SIK1), a member of the AMP-activated protein kinase (AMPK) family, in the regulation of MEF2-mediated transcription by the neurotrophin brain-derived neurotrophic factor (BDNF). We show that BDNF increases the expression of SIK1 in primary cultures of rat cortical neurons through the extracellular signal-regulated kinase 1/2 (ERK1/2)-signaling pathway. In addition to inducing SIK1 expression, BDNF triggers the phosphorylation of SIK1 at Thr182 and its translocation from the cytoplasm to the nucleus of cortical neurons. The effects of BDNF on the expression, phosphorylation and, translocation of SIK1 are followed by the phosphorylation and nuclear export of histone deacetylase 5 (HDAC5). Blockade of SIK activity with a low concentration of staurosporine abolished BDNF-induced phosphorylation and nuclear export of HDAC5 in cortical neurons. Importantly, stimulation of HDAC5 phosphorylation and nuclear export by BDNF is accompanied by the activation of MEF2-mediated transcription, an effect that is suppressed by staurosporine. Consistent with these data, BDNF induces the expression of the MEF2 target genes Arc and Nur77, in a staurosporine-sensitive manner. In further support of the role of SIK1 in the regulation of MEF2-dependent transcription by BDNF, we found that expression of wild-type SIK1 or S577A SIK1, a mutated form of SIK1 which is retained in the nucleus of transfected cells, is sufficient to enhance MEF2 transcriptional activity in cortical neurons. Together, these data identify a previously unrecognized mechanism by which SIK1 mediates the activation of MEF2-dependent transcription by BDNF. © 2013 Finsterwald et al.

Giuliani F.,University of Lausanne | Schenk F.,University of Lausanne | Schenk F.,Center for Psychiatric Neuroscience
Research in Developmental Disabilities | Year: 2015

Vision is the most synthetic sensory channel and it provides specific information about the relative position of distant landmarks during visual exploration. In this paper we propose that visual exploration, as assessed by the recording of eye movements, offers an original method to analyze spatial cognition and to reveal alternative adaptation strategies in people with intellectual disabilities (ID). Our general assumption is that eye movement exploration may simultaneously reveal whether, why, and how, compensatory strategies point to specific difficulties related to neurological symptoms. An understanding of these strategies will also help in the development of optimal rehabilitation procedures. © 2014 Elsevier Ltd.

Petit J.-M.,Ecole Polytechnique Federale de Lausanne | Petit J.-M.,Center for Psychiatric Neuroscience | Burlet-Godinot S.,Ecole Polytechnique Federale de Lausanne | Magistretti P.J.,Ecole Polytechnique Federale de Lausanne | And 2 more authors.
Metabolic Brain Disease | Year: 2014

In 1995 Benington and Heller formulated an energy hypothesis of sleep centered on a key role of glycogen. It was postulated that a major function of sleep is to replenish glycogen stores in the brain that have been depleted during wakefulness which is associated to an increased energy demand. Astrocytic glycogen depletion participates to an increase of extracellular adenosine release which influences sleep homeostasis. Here, we will review some evidence obtained by studies addressing the question of a key role played by glycogen metabolism in sleep regulation as proposed by this hypothesis or by an alternative hypothesis named “glycogenetic” hypothesis as well as the importance of the confounding effect of glucocorticoïds. Even though actual collected data argue in favor of a role of sleep in brain energy balance-homeostasis, they do not support a critical and direct involvement of glycogen metabolism on sleep regulation. For instance, glycogen levels during the sleep-wake cycle are driven by different physiological signals and therefore appear more as a marker-integrator of brain energy status than a direct regulator of sleep homeostasis. In support of this we provide evidence that blockade of glycogen mobilization does not induce more sleep episodes during the active period while locomotor activity is reduced. These observations do not invalidate the energy hypothesis of sleep but indicate that underlying cellular mechanisms are more complex than postulated by Benington and Heller. © 2014, The Author(s).

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