Publications by authors named "Hamid Meziane"

40 Publications

Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models.

Hum Mol Genet 2021 Mar 9. Epub 2021 Mar 9.

Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France.

Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype-phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging (MRI) and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 21 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted 6 biological cascades centred around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.
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http://dx.doi.org/10.1093/hmg/ddab012DOI Listing
March 2021

BAHD1 haploinsufficiency results in anxiety-like phenotypes in male mice.

PLoS One 2020 14;15(5):e0232789. Epub 2020 May 14.

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France.

BAHD1 is a heterochomatinization factor recently described as a component of a multiprotein complex associated with histone deacetylases HDAC1/2. The physiological and patho-physiological functions of BAHD1 are not yet well characterized. Here, we examined the consequences of BAHD1 deficiency in the brains of male mice. While Bahd1 knockout mice had no detectable defects in brain anatomy, RNA sequencing profiling revealed about 2500 deregulated genes in Bahd1-/- brains compared to Bahd1+/+ brains. A majority of these genes were involved in nervous system development and function, behavior, metabolism and immunity. Exploration of the Allen Brain Atlas and Dropviz databases, assessing gene expression in the brain, revealed that expression of the Bahd1 gene was limited to a few territories and cell subtypes, particularly in the hippocampal formation, the isocortex and the olfactory regions. The effect of partial BAHD1 deficiency on behavior was then evaluated on Bahd1 heterozygous male mice, which have no lethal or metabolic phenotypes. Bahd1+/- mice showed anxiety-like behavior and reduced prepulse inhibition (PPI) of the startle response. Altogether, these results suggest that BAHD1 plays a role in chromatin-dependent gene regulation in a subset of brain cells and support recent evidence linking genetic alteration of BAHD1 to psychiatric disorders in a human patient.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232789PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224496PMC
July 2020

Antinociceptive effects of potent, selective and brain penetrant muscarinic M positive allosteric modulators in rodent pain models.

Brain Res 2020 06 29;1737:146814. Epub 2020 Mar 29.

Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.

Analgesic properties of orthosteric agonists of the muscarinic M receptor subtype have been documented in literature reports, with evidence from pharmacological and in vivo receptor knock out (KO) studies. Constitutive M receptor KO mice demonstrated an increased response in the formalin pain model, supporting this hypothesis. Two novel positive allosteric modulators (PAM) of the M receptor, Compounds 1 and 2, were characterized in rodent models of acute nociception. Results indicated decreased time spent on nociceptive behaviors in the mouse formalin model, and efficacy in the mouse tail flick assay. The analgesic-like effects of Compounds 1 and 2 were shown to be on target, as the compounds lacked any activity in constitutive M KO mice, while retaining activity in wild type control littermates. The analgesic-like effects of Compounds 1 and 2 were significantly diminished in KO mice that have selective deletion of the M receptor in neurons that co-express the dopaminergic D receptor subtype, suggesting a centrally-mediated effect on nociception. The opioid antagonist naloxone did not diminish the effect of Compound 1, indicating the effects of Compound 1 are not secondarily linked to opioid pathways. Compound 1 was evaluated in the rat, where it demonstrated analgesic-like effects in tail flick and a subpopulation of spinal nociceptive sensitive neurons, suggesting some involvement of spinal mechanisms of nociceptive modulation. These studies indicate that M PAMs may be a tractable target for pain management assuming an appropriate safety profile, and it appears likely that both spinal and supraspinal pathways may mediate the antinociceptive-like effects.
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http://dx.doi.org/10.1016/j.brainres.2020.146814DOI Listing
June 2020

Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny.

Hum Mol Genet 2020 03;29(5):766-784

Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France.

By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model, we investigated RosaCre-, NestinCre- and NexCre-driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that the expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A.
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http://dx.doi.org/10.1093/hmg/ddz316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104682PMC
March 2020

Soft windowing application to improve analysis of high-throughput phenotyping data.

Bioinformatics 2020 03;36(5):1492-1500

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Motivation: High-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors.

Results: Here we introduce 'soft windowing', a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources.

Availability And Implementation: The method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115897PMC
March 2020

Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Commun Biol 2019 7;2:97. Epub 2019 Mar 7.

Department of Ophthalmology & Vision Science, School of Medicine, U.C. Davis, Sacramento, CA, 95817, USA.

[This corrects the article DOI: 10.1038/s42003-018-0226-0.].
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http://dx.doi.org/10.1038/s42003-019-0349-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405960PMC
March 2019

Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Commun Biol 2018 21;1:236. Epub 2018 Dec 21.

Department of Ophthalmology & Vision Science, School of Medicine, U.C. Davis, Sacramento, CA, 95817, USA.

Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease.
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http://dx.doi.org/10.1038/s42003-018-0226-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303268PMC
December 2018

A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations.

Hum Mol Genet 2018 06;27(12):2138-2153

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 67404 Illkirch, France.

The aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans, among which the most frequent, a 24 bp duplication in the polyalanine tract 2 (c.428_451dup24), gives rise to intellectual disability, fine motor defects with or without epilepsy. To understand the functional consequences of this mutation, we generated a partially humanized mouse model carrying the c.428_451dup24 duplication (Arxdup24/0) that we characterized at the behavior, neurological and molecular level. Arxdup24/0 males presented with hyperactivity, enhanced stereotypies and altered contextual fear memory. In addition, Arxdup24/0 males had fine motor defects with alteration of reaching and grasping abilities. Transcriptome analysis of Arxdup24/0 forebrains at E15.5 showed a down-regulation of genes specific to interneurons and an up-regulation of genes normally not expressed in this cell type, suggesting abnormal interneuron development. Accordingly, interneuron migration was altered in the cortex and striatum between E15.5 and P0 with consequences in adults, illustrated by the defect in the inhibitory/excitatory balance in Arxdup24/0 basolateral amygdala. Altogether, we showed that the c.428_451dup24 mutation disrupts Arx function with a direct consequence on interneuron development, leading to hyperactivity and defects in precise motor movement control and associative memory. Interestingly, we highlighted striking similarities between the mouse phenotype and a cohort of 33 male patients with ARX c.428_451dup24, suggesting that this new mutant mouse line is a good model for understanding the pathophysiology and evaluation of treatment.
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http://dx.doi.org/10.1093/hmg/ddy122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985730PMC
June 2018

Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome.

Nucleic Acids Res 2018 06;46(10):4950-4965

Radboud University, Department of Molecular Biology, Faculty of Science, 6500 HB Nijmegen, the Netherlands.

Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/- adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/- mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/- mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/- mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.
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http://dx.doi.org/10.1093/nar/gky196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007260PMC
June 2018

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction.

Nat Commun 2017 10 12;8(1):886. Epub 2017 Oct 12.

Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK.

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function.The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.
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http://dx.doi.org/10.1038/s41467-017-00595-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638796PMC
October 2017

Synaptic dysfunction in amygdala in intellectual disorder models.

Prog Neuropsychopharmacol Biol Psychiatry 2018 06 1;84(Pt B):392-397. Epub 2017 Aug 1.

Team "synapse in cognition", UMR 5297, University of Bordeaux, Bordeaux, France; Team "synapse in cognition", UMR 5297, Centre National de la recherche scientifique, Bordeaux, France. Electronic address:

The amygdala is a part of the limbic circuit that has been extensively studied in terms of synaptic connectivity, plasticity and cellular organization since decades (Ehrlich et al., 2009; Ledoux, 2000; Maren, 2001). Amygdala sub-nuclei, including lateral, basolateral and central amygdala appear now as "hubs" providing in parallel and in series neuronal processing enabling the animal to elicit freezing or escaping behavior in response to external threats. In rodents, these behaviors are easily observed and quantified following associative fear conditioning. Thus, studies on amygdala circuit in association with threat/fear behavior became very popular in laboratories and are often used among other behavioral tests to evaluate learning abilities of mouse models for various neuropsychiatric conditions including genetically encoded intellectual disabilities (ID). Yet, more than 100 human X-linked genes - and several hundreds of autosomal genes - have been associated with ID in humans. These mutations introduced in mice can generate social deficits, anxiety dysregulations and fear learning impairments (McNaughton et al., 2008; Houbaert et al., 2013; Jayachandran et al., 2014; Zhang et al., 2015). Noteworthy, a significant proportion of the coded ID gene products are synaptic proteins. It is postulated that the loss of function of these proteins could destabilize neuronal circuits by global changes of the balance between inhibitory and excitatory drives onto neurons. However, whereas amygdala related behavioral deficits are commonly observed in ID models, the role of most of these ID-genes in synaptic function and plasticity in the amygdala are only sparsely studied. We will here discuss some of the concepts that emerged from amygdala-targeted studies examining the role of syndromic and non-syndromic ID genes in fear-related behaviors and/or synaptic function. Along describing these cases, we will discuss how synaptic deficits observed in amygdala circuits could impact memory formation and expression of conditioned fear.
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http://dx.doi.org/10.1016/j.pnpbp.2017.07.028DOI Listing
June 2018

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition.

PLoS Genet 2017 Jul 13;13(7):e1006886. Epub 2017 Jul 13.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France.

Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.
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http://dx.doi.org/10.1371/journal.pgen.1006886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531616PMC
July 2017

RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents.

Neuropharmacology 2017 05 10;118:188-198. Epub 2017 Mar 10.

Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address:

Although opiates represent the most effective analgesics, their use in chronic treatments is associated with numerous side effects including the development of pain hypersensitivity and analgesic tolerance. We recently identified a novel orally active neuropeptide FF (NPFF) receptor antagonist, RF313, which efficiently prevents the development of fentanyl-induced hyperalgesia in rats. In this study, we investigated the properties of this compound into more details. We show that RF313 exhibited a pronounced selectivity for NPFF receptors, antagonist activity at NPFF1 receptor (NPFF1R) subtype both in vitro and in vivo and no major side effects when administered in mice up to 30 mg/kg. When co-administered with opiates in rats and mice, it improved their analgesic efficacy and prevented the development of long lasting opioid-induced hyperalgesia. Moreover, and in marked contrast with the dipeptidic NPFF receptor antagonist RF9, RF313 displayed negligible affinity and no agonist activity (up to 100 μM) toward the kisspeptin receptor. Finally, in male hamster, RF313 had no effect when administered alone but fully blocked the increase in LH induced by RFRP-3, while RF9 per se induced a significant increase in LH levels which is consistent with its ability to activate kisspeptin receptors. Altogether, our data indicate that RF313 represents an interesting compound for the development of therapeutic tools aiming at improving analgesic action of opiates and reducing adverse side effects associated with their chronic administration. Moreover, its lack of agonist activity at the kisspeptin receptor indicates that RF313 might be considered a better pharmacological tool, when compared to RF9, to examine the regulatory roles of RF-amide-related peptides and NPFF1R in reproduction.
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http://dx.doi.org/10.1016/j.neuropharm.2017.03.012DOI Listing
May 2017

Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome.

Neuron 2017 Jan 5;93(2):331-347. Epub 2017 Jan 5.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France; Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France. Electronic address:

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5' UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.
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http://dx.doi.org/10.1016/j.neuron.2016.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263258PMC
January 2017

Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability.

Hum Mol Genet 2016 06 4;25(11):2314-2323. Epub 2016 May 4.

Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, 75014, France

Loss of function mutations in human Oligophrenin1 (OPHN1) gene are responsible for syndromic intellectual disability (ID) associated with cerebellar hypoplasia and cerebral ventricles enlargement. Functional studies in rodent models suggest that OPHN1 linked ID is a consequence of abnormal synaptic transmission and shares common pathophysiological mechanisms with other cognitive disorders. Variants of this gene have been also identified in autism spectrum disorder and schizophrenia. The advanced understanding of the mechanisms underlying OPHN1-related ID, allowed us to develop a therapeutic approach targeting the Ras homolog gene family, member A (RHOA) signalling pathway and repurpose Fasudil- a well-tolerated Rho Kinase (ROCK) and Protein Kinase A (PKA) inhibitor- as a treatment of ID. We have previously shown ex-vivo its beneficial effect on synaptic transmission and plasticity in a mouse model of the OPHN1 loss of function. Here, we report that chronic treatment in adult mouse with Fasudil, is able to counteract vertical and horizontal hyperactivities, restores recognition memory and limits the brain ventricular dilatation observed in Ophn1 However, deficits in working and spatial memories are partially or not rescued by the treatment. These results highlight the potential of Fasudil treatment in synaptopathies and also the need for multiple therapeutic approaches especially in adult where brain plasticity is reduced.
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http://dx.doi.org/10.1093/hmg/ddw102DOI Listing
June 2016

Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome.

Proc Natl Acad Sci U S A 2015 Dec 16;112(48):E6691-8. Epub 2015 Nov 16.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964; University of Strasbourg Institute for Advanced Study, Collège de France, Illkirch 67404, France

The light-entrained master central circadian clock (CC) located in the suprachiasmatic nucleus (SCN) not only controls the diurnal alternance of the active phase (the light period of the human light-dark cycle, but the mouse dark period) and the rest phase (the human dark period, but the mouse light period), but also synchronizes the ubiquitous peripheral CCs (PCCs) with these phases to maintain homeostasis. We recently elucidated in mice the molecular signals through which metabolic alterations induced on an unusual feeding schedule, taking place during the rest phase [i.e., restricted feeding (RF)], creates a 12-h PCC shift. Importantly, a previous study showed that the SCN CC is unaltered during RF, which creates a misalignment between the RF-shifted PCCs and the SCN CC-controlled phases of activity and rest. However, the molecular basis of SCN CC insensitivity to RF and its possible pathological consequences are mostly unknown. Here we deciphered, at the molecular level, how RF creates this misalignment. We demonstrate that the PPARα and glucagon receptors, the two instrumental transducers in the RF-induced shift of PCCs, are not expressed in the SCN, thereby preventing on RF a shift of the master SCN CC and creating the misalignment. Most importantly, this RF-induced misalignment leads to a misexpression (with respect to their normal physiological phase of expression) of numerous CC-controlled homeostatic genes, which in the long term generates in RF mice a number of metabolic pathologies including diabetes, obesity, and metabolic syndrome, which have been reported in humans engaged in shift work schedules.
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http://dx.doi.org/10.1073/pnas.1519807112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672793PMC
December 2015

Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes.

Hum Mol Genet 2016 Jan 24;25(1):146-57. Epub 2015 Nov 24.

Inserm, U1016, Institut Cochin, Paris, France, Cnrs, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Laboratoire de Biologie et Génétique Moléculaires, HUPC, Hôpital Cochin, Paris, France,

Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder, characterized by normal post-natal development followed by a sudden deceleration in brain growth with progressive loss of acquired motor and language skills, stereotypic hand movements and severe cognitive impairment. Mutations in the methyl-CpG-binding protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, and that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern and greatly prolonged lifespan compared with globally null mice. We now report that microtubule (MT)-dependent vesicle transport is altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared with control wild-type littermates. Similar observation has been made in human MECP2 p.Arg294* iPSC-derived astrocytes. Importantly, administration of Epothilone D, a brain-penetrant MT-stabilizing natural product, was found to restore MT dynamics in Mecp2-deficient astrocytes and in MECP2 p.Arg294* iPSC-derived astrocytes in vitro. Finally, we report that relatively low weekly doses of Epothilone D also partially reversed the impaired exploratory behavior in Mecp2(308/y) male mice. These findings represent a first step toward the validation of an innovative treatment for RTT.
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http://dx.doi.org/10.1093/hmg/ddv464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690499PMC
January 2016

Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.

Hum Mol Genet 2015 Dec 16;24(23):6736-55. Epub 2015 Sep 16.

Institut Clinique de la Souris, PHENOMIN, GIE CERBM, 1 rue Laurent Fries, 67404 Illkirch, France, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France, Centre National de la Recherche Scientifique, UMR7104, Illkirch, France, Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France and Université de Strasbourg, Illkirch, France

ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2(Camk2aCre/0) mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2(Camk2aCre/0) mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2(Camk2aCre/0) mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2(Camk2aCre/0) mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system.
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http://dx.doi.org/10.1093/hmg/ddv380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634377PMC
December 2015

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

Authors:
Martin Hrabě de Angelis George Nicholson Mohammed Selloum Jacqui White Hugh Morgan Ramiro Ramirez-Solis Tania Sorg Sara Wells Helmut Fuchs Martin Fray David J Adams Niels C Adams Thure Adler Antonio Aguilar-Pimentel Dalila Ali-Hadji Gregory Amann Philippe André Sarah Atkins Aurelie Auburtin Abdel Ayadi Julien Becker Lore Becker Elodie Bedu Raffi Bekeredjian Marie-Christine Birling Andrew Blake Joanna Bottomley Mike Bowl Véronique Brault Dirk H Busch James N Bussell Julia Calzada-Wack Heather Cater Marie-France Champy Philippe Charles Claire Chevalier Francesco Chiani Gemma F Codner Roy Combe Roger Cox Emilie Dalloneau André Dierich Armida Di Fenza Brendan Doe Arnaud Duchon Oliver Eickelberg Chris T Esapa Lahcen El Fertak Tanja Feigel Irina Emelyanova Jeanne Estabel Jack Favor Ann Flenniken Alessia Gambadoro Lilian Garrett Hilary Gates Anna-Karin Gerdin George Gkoutos Simon Greenaway Lisa Glasl Patrice Goetz Isabelle Goncalves Da Cruz Alexander Götz Jochen Graw Alain Guimond Wolfgang Hans Geoff Hicks Sabine M Hölter Heinz Höfler John M Hancock Robert Hoehndorf Tertius Hough Richard Houghton Anja Hurt Boris Ivandic Hughes Jacobs Sylvie Jacquot Nora Jones Natasha A Karp Hugo A Katus Sharon Kitchen Tanja Klein-Rodewald Martin Klingenspor Thomas Klopstock Valerie Lalanne Sophie Leblanc Christoph Lengger Elise le Marchand Tonia Ludwig Aline Lux Colin McKerlie Holger Maier Jean-Louis Mandel Susan Marschall Manuel Mark David G Melvin Hamid Meziane Kateryna Micklich Christophe Mittelhauser Laurent Monassier David Moulaert Stéphanie Muller Beatrix Naton Frauke Neff Patrick M Nolan Lauryl Mj Nutter Markus Ollert Guillaume Pavlovic Natalia S Pellegata Emilie Peter Benoit Petit-Demoulière Amanda Pickard Christine Podrini Paul Potter Laurent Pouilly Oliver Puk David Richardson Stephane Rousseau Leticia Quintanilla-Fend Mohamed M Quwailid Ildiko Racz Birgit Rathkolb Fabrice Riet Janet Rossant Michel Roux Jan Rozman Ed Ryder Jennifer Salisbury Luis Santos Karl-Heinz Schäble Evelyn Schiller Anja Schrewe Holger Schulz Ralf Steinkamp Michelle Simon Michelle Stewart Claudia Stöger Tobias Stöger Minxuan Sun David Sunter Lydia Teboul Isabelle Tilly Glauco P Tocchini-Valentini Monica Tost Irina Treise Laurent Vasseur Emilie Velot Daniela Vogt-Weisenhorn Christelle Wagner Alison Walling Bruno Weber Olivia Wendling Henrik Westerberg Monja Willershäuser Eckhard Wolf Anne Wolter Joe Wood Wolfgang Wurst Ali Önder Yildirim Ramona Zeh Andreas Zimmer Annemarie Zimprich Chris Holmes Karen P Steel Yann Herault Valérie Gailus-Durner Ann-Marie Mallon Steve Dm Brown

Nat Genet 2015 Sep 27;47(9):969-978. Epub 2015 Jul 27.

MRC Harwell, Medical Research Council, Harwell, UK.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
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http://dx.doi.org/10.1038/ng.3360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564951PMC
September 2015

An Early Postnatal Oxytocin Treatment Prevents Social and Learning Deficits in Adult Mice Deficient for Magel2, a Gene Involved in Prader-Willi Syndrome and Autism.

Biol Psychiatry 2015 Jul 20;78(2):85-94. Epub 2014 Nov 20.

Institut de Neurobiologie de la Méditerranée; Aix-Marseille Université, Marseille. Electronic address:

Background: Mutations of MAGEL2 have been reported in patients presenting with autism, and loss of MAGEL2 is also associated with Prader-Willi syndrome, a neurodevelopmental genetic disorder. This study aimed to determine the behavioral phenotype of Magel2-deficient adult mice, to characterize the central oxytocin (OT) system of these mutant mice, and to test the curative effect of a peripheral OT treatment just after birth.

Methods: We assessed the social and cognitive behavior of Magel2-deficient mice, analyzed the OT system of mutant mice treated or not by a postnatal administration of OT, and determined the effect of this treatment on the brain.

Results: Magel2 inactivation induces a deficit in social recognition and social interaction and a reduced learning ability in adult male mice. In these mice, we reveal anatomical and functional modifications of the OT system and show that these defects change from birth to adulthood. Daily administration of OT in the first postnatal week was sufficient to prevent deficits in social behavior and learning abilities in adult mutant male mice. We show that this OT treatment partly restores a normal OT system. Thus, we report that an alteration of the OT system around birth has long-term consequences on behavior and on cognition. Importantly, an acute OT treatment of Magel2-deficient pups has a curative effect.

Conclusions: Our study reveals that OT plays a crucial role in setting social behaviors during a period just after birth. An early OT treatment in this critical period could be a novel therapeutic approach for the treatment of neurodevelopmental disorders such as Prader-Willi syndrome and autism.
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http://dx.doi.org/10.1016/j.biopsych.2014.11.010DOI Listing
July 2015

Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice.

Oncotarget 2014 May;5(9):2703-13

Inserm U830, Paris, France;

The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058038PMC
http://dx.doi.org/10.18632/oncotarget.1882DOI Listing
May 2014

Impact of the apolipoprotein E polymorphism, age and sex on neurogenesis in mice: pathophysiological relevance for Alzheimer's disease?

Brain Res 2014 Jan 16;1542:32-40. Epub 2013 Oct 16.

Institut Clinique de la Souris (ICS), Phenomin, Illkirch, France. Electronic address:

Apolipoprotein E (ApoE) is found in three different forms in humans (ApoE2, ApoE3 and ApoE4), and ApoE polymorphism is recognized as a major risk factor for Alzheimer's disease (AD). ApoE is involved in lipid and cholesterol transport, cell repair, and amyloid-β deposition and certain studies suggest potential implications in neurogenesis. In this regard, we investigated the possible impact of the three different human ApoE isoforms on neurogenesis. We used ApoE knock-in mice of different ages and sex, and quantified newborn cells in the hippocampus by flow cytometry. Young adult ApoE4 mice (10-12 week-old) from both sexes displayed reduced neurogenesis compared with wild-types and the other genotypes. In addition, young adult ApoE2 female mice showed improved hippocampal progenitor cell proliferation. In older mice (1 year), hippocampal neurogenesis was globally decreased, particularly in females, and the difference between ApoE4 and the other genotypes observed in young animals disappeared for the two sexes, except for aged ApoE3 females. Indeed, a surprising protective effect of the ApoE3 genotype was observed in aged females. Our study highlights the role of ApoE in neurogenesis, and shows for the first time an early inequality between the ApoE genotypes. The reduced neurogenesis observed for the ApoE4 genotype and the improved results obtained in young ApoE2 females support the idea of a difference in the balance between neuronal birth and death modulated by the ApoE polymorphism in young animals. The maintenance of this balance and its modulation can influence pathophysiological mechanisms predisposing to neurodegenerative diseases like AD.
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http://dx.doi.org/10.1016/j.brainres.2013.10.003DOI Listing
January 2014

The homeodomain factor Gbx1 is required for locomotion and cell specification in the dorsal spinal cord.

PeerJ 2013 29;1:e142. Epub 2013 Aug 29.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch Cedex, France.

Dorsal horn neurons in the spinal cord integrate and relay sensory information to higher brain centers. These neurons are organized in specific laminae and different transcription factors are involved in their specification. The murine homeodomain Gbx1 protein is expressed in the mantle zone of the spinal cord at E12.5-13.5, correlating with the appearance of a discernable dorsal horn around E14 and eventually defining a narrow layer in the dorsal horn around perinatal stages. At postnatal stages, Gbx1 identifies a specific subpopulation of GABAergic neurons in the dorsal spinal cord. We have generated a loss of function mutation for Gbx1 and analyzed its consequences during spinal cord development. Gbx1 (-/-) mice are viable and can reproduce as homozygous null mutants. However, the adult mutant mice display an altered gait during forward movement that specifically affects the hindlimbs. This abnormal gait was evaluated by a series of behavioral tests, indicating that locomotion is impaired, but not muscle strength or motor coordination. Molecular analysis showed that the development of the dorsal horn is not profoundly affected in Gbx1 (-/-) mutant mice. However, analysis of terminal neuronal differentiation revealed that the proportion of GABAergic inhibitory interneurons in the superficial dorsal horn is diminished. Our study unveiled a role for Gbx1 in specifying a subset of GABAergic neurons in the dorsal horn of the spinal cord involved in the control of posterior limb movement.
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http://dx.doi.org/10.7717/peerj.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757465PMC
September 2013

Endogenous mammalian RF-amide peptides, including PrRP, kisspeptin and 26RFa, modulate nociception and morphine analgesia via NPFF receptors.

Neuropharmacology 2013 Dec 2;75:164-71. Epub 2013 Aug 2.

Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Medalis, Illkirch, France. Electronic address:

Mammalian RF-amide peptides are encoded by five different genes and act through five different G protein-coupled receptors. RF-amide-related peptides-1 and -3, neuropeptides AF and FF, Prolactin releasing peptides, Kisspeptins and RFa peptides are currently considered endogenous peptides for NPFF1, NPFF2, GPR10, GPR54 and GPR103 receptors, respectively. However, several studies suggest that the selectivity of these peptides for their receptors is low and indicate that expression patterns for receptors and their corresponding ligands only partially overlap. In this study, we took advantage of the cloning of the five human RF-amide receptors to systematically examine their affinity for and their activation by all human RF-amide peptides. Binding experiments, performed on membranes from CHO cells expressing GPR10, GPR54 and GPR103 receptors, confirmed their high affinity and remarkable selectivity for their cognate ligands. Conversely, NPFF1 and NPFF2 receptors displayed high affinity for all RF-amide peptides. Moreover, GTPγS and cAMP experiments showed that almost all RF-amide peptides efficiently activate NPFF1 and NPFF2 receptors. As NPFF is known to modulate morphine analgesia, we undertook a systematic analysis in mice of the hyperalgesic and anti morphine-induced analgesic effects of a representative set of endogenous RF-amide peptides. All of them induced hyperalgesia and/or prevented morphine analgesia following intracerebroventricular administration. Importantly, these effects were prevented by administration of RF9, a highly selective NPFF1/NPFF2 antagonist. Altogether, our results show that all endogenous RF-amide peptides display pain-modulating properties and point to NPFF receptors as essential players for these effects.
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http://dx.doi.org/10.1016/j.neuropharm.2013.07.012DOI Listing
December 2013

A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains.

Genome Biol 2013 Jul 31;14(7):R82. Epub 2013 Jul 31.

Background: The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms.

Results: We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems.

Conclusions: Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.
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http://dx.doi.org/10.1186/gb-2013-14-7-r82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053787PMC
July 2013

Estrogen dependent activation function of ERβ is essential for the sexual behavior of mouse females.

Proc Natl Acad Sci U S A 2012 Nov 12;109(48):19822-7. Epub 2012 Nov 12.

Institut d'Histologie, Faculté de Médecine, Université de Strasbourg, 67085 Strasbourg, France.

We previously generated and characterized a genuine estrogen receptor (ER) β-null mouse line (named ERβ(ST)(L-/L-)) and showed that ERβ(ST)(L-/L-) mice were sterile, due to an ovulation impairment in females and to an unknown reason in males, as their reproductive organs and spermatozoid motility appeared normal. We report here an assessment of the sexual behavior of ERβ(ST)(L-/L-) null mice. We found that ERβ(ST)(L-/L-) males display mildly impaired sexual behavior and that ERβ(ST)(L-/L-) females are significantly less receptive and less attractive than wild-type (WT) females. Decreased attractivity is also exhibited by ERβAF2(0) but not by ERβAF1(0) mutant females (females devoid of either AF2 or AF1 activation function of ERβ). Interestingly, by using an odor preference test, we have determined that the low attractiveness of ERβ(ST)(L-/L-) and ERβAF2(0) females is related to a deficiency of a volatile chemosignal.
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http://dx.doi.org/10.1073/pnas.1217668109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511745PMC
November 2012

Absence of TI-VAMP/Vamp7 leads to increased anxiety in mice.

J Neurosci 2012 Feb;32(6):1962-8

Program in Development and Neurobiology, Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, F-75205 Paris, France.

Vesicular (v)- and target (t)-SNARE proteins assemble in SNARE complex to mediate membrane fusion. Tetanus neurotoxin-insensitive vesicular-associated membrane protein (TI-VAMP/VAMP7), a vesicular SNARE expressed in several cell types including neurons, was previously shown to play a major role in exocytosis involved in neurite growth in cultured neurons. Here we generated a complete constitutive knock-out by deleting the exon 3 of Vamp7. Loss of TI-VAMP expression did not lead to any striking developmental or neurological defect. Knock-out mice displayed decreased brain weight and increased third ventricle volume. Axon growth appeared normal in cultured knock-out neurons. Behavioral characterization unraveled that TI-VAMP knock-out was associated with increased anxiety. Our results thus suggest compensatory mechanisms allowing the TI-VAMP knock-out mice to fulfill major developmental processes. The phenotypic traits unraveled here further indicate an unexpected role of TI-VAMP-mediated vesicular traffic in anxiety and suggest a role for TI-VAMP in higher brain functions.
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http://dx.doi.org/10.1523/JNEUROSCI.4436-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621696PMC
February 2012

Acoustic Startle Reflex and Prepulse Inhibition.

Curr Protoc Mouse Biol 2012 Mar 1;2(1):25-35. Epub 2012 Mar 1.

Institut Clinique de la Souris (ICS), Illkirch, France.

The completion of genome sequencing in humans and mice has opened new opportunities to study the relationship between gene expression and behavior and for development of novel therapeutic approaches for brain diseases. Recently, several international programs for large-scale production and phenotyping of genetically modified mice have been launched (e.g., EUCOMM, EUMODIC, IMPC), and comprehensive high-throughput behavioral phenotyping strategies have been developed (EUMORPHIA). In this context, startle reflex represents an important research tool for studying the impact of genetic manipulations not only on sensory processes but also on complex brain functions such as cognition, emotions, and movement control. In this unit, step-by-step protocols for measurement of acoustic startle reactivity and prepulse inhibition of startle in mice are described, and supporting experimental data presented. Curr. Protoc. Mouse Biol. 2:25-35 © 2012 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/9780470942390.mo110132DOI Listing
March 2012

TASK-3 as a potential antidepressant target.

Brain Res 2011 Oct 16;1416:69-79. Epub 2011 Aug 16.

Department of Neuroscience, Merck Research Laboratories, West Point, PA, USA.

Modulation of TASK-3 (Kcnk9) potassium channels affect neurotransmitter release in thalamocortical centers and other sleep-related nuclei having the capacity to regulate arousal cycles and REM sleep changes associated with mood disorders and antidepressant action. Circumstantial evidence from this and previous studies suggest the potential for TASK-3 to be a novel antidepressant therapeutic target; TASK-3 knock-out mice display augmented circadian amplitude and exhibit sleep architecture characterized by suppressed REM activity. Detailed analysis of locomotor activity indicates that the amplitudes of activity bout duration and bout number are augmented in TASK-3 mutants well beyond that seen in wildtypes, findings substantiated by amplitude increases in body temperature and EEG recordings of sleep stage bouts. Polysomnographic analysis of TASK-3 mutants reveals increases in nocturnal active wake and suppressed REM sleep time while increased slow wave sleep typifies the inactive phase, findings that have implications for the cognitive impact of reduced TASK-3 activity. In direct measures of their resistance to despair behavior, TASK-3 knock-outs displayed significant decreases in immobility relative to wildtype controls in both tail suspension and forced swim tests. Treatment of wildtype animals with the antidepressant Fluoxetine markedly reduced REM sleep, while leaving active wake and slow wave sleep relatively intact. Remarkably, these effects were absent in TASK-3 mutants indicating that TASK-3 is either directly involved in the mechanism of this drug's action, or participates in parallel pathways that achieve the same effect. Together, these results support the TASK-3 channel to act as a therapeutic target for antidepressant action.
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http://dx.doi.org/10.1016/j.brainres.2011.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179828PMC
October 2011

EuroPhenome: a repository for high-throughput mouse phenotyping data.

Nucleic Acids Res 2010 Jan 23;38(Database issue):D577-85. Epub 2009 Nov 23.

MRC Harwell, Mammalian Genetics Unit, MRC Harwell, Mary Lyon Centre, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.

The broad aim of biomedical science in the postgenomic era is to link genomic and phenotype information to allow deeper understanding of the processes leading from genomic changes to altered phenotype and disease. The EuroPhenome project (http://www.EuroPhenome.org) is a comprehensive resource for raw and annotated high-throughput phenotyping data arising from projects such as EUMODIC. EUMODIC is gathering data from the EMPReSSslim pipeline (http://www.empress.har.mrc.ac.uk/) which is performed on inbred mouse strains and knock-out lines arising from the EUCOMM project. The EuroPhenome interface allows the user to access the data via the phenotype or genotype. It also allows the user to access the data in a variety of ways, including graphical display, statistical analysis and access to the raw data via web services. The raw phenotyping data captured in EuroPhenome is annotated by an annotation pipeline which automatically identifies statistically different mutants from the appropriate baseline and assigns ontology terms for that specific test. Mutant phenotypes can be quickly identified using two EuroPhenome tools: PhenoMap, a graphical representation of statistically relevant phenotypes, and mining for a mutant using ontology terms. To assist with data definition and cross-database comparisons, phenotype data is annotated using combinations of terms from biological ontologies.
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http://dx.doi.org/10.1093/nar/gkp1007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808931PMC
January 2010