Neurocentre Magendie

Mélanie GINGER




ITA

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Cursus:
Ingénieur d'étude

Expertise: cortical circuits, viral tracing





9 publication(s) depuis Décembre 2001:


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* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en


11/2015 | sci adv
Structural-functional connectivity deficits of neocortical circuits in the Fmr1 (-/y) mouse model of autism.
Haberl MG, Zerbi V, Veltien A, Ginger M, Heerschap A, Frick A

Abstract:
Fragile X syndrome (FXS), the most common inherited form of intellectual disability disorder and a frequent cause of autism spectrum disorder (ASD), is characterized by a high prevalence of sensory symptoms. Perturbations in the anatomical connectivity of neocortical circuits resulting in their functional defects have been hypothesized to contribute to the underlying etiology of these disorders. We tested this idea by probing alterations in the functional and structural connectivity of both local and long-ranging neocortical circuits in the Fmr1 (-/y) mouse model of FXS. To achieve this, we combined in vivo ultrahigh-field diffusion tensor magnetic resonance imaging (MRI), functional MRI, and viral tracing approaches in adult mice. Our results show an anatomical hyperconnectivity phenotype for the primary visual cortex (V1), but a disproportional low connectivity of V1 with other neocortical regions. These structural data are supported by defects in the structural integrity of the subcortical white matter in the anterior and posterior forebrain. These anatomical alterations might contribute to the observed functional decoupling across neocortical regions. We therefore identify FXS as a 'connectopathy,' providing a translational model for understanding sensory processing defects and functional decoupling of neocortical areas in FXS and ASD.




10/11/2014 | Nat Neurosci   IF 16.7
Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1 mice.
Zhang Y*, Bonnan A*, Bony G*, Ferezou I, Pietropaolo S, Ginger M, Sans N, Rossier J, Oostra B, Lemasson G, Frick A

Abstract:
Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1-/y mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.




11/04/2014 | Brain Struct Funct   IF 5.8
An anterograde rabies virus vector for high-resolution large-scale reconstruction of 3D neuron morphology.
Haberl MG*, Viana da Silva S*, Guest JM, Ginger M, Ghanem A, Mulle C, Oberlaender M, Conzelmann KK, Frick A

Abstract:
Glycoprotein-deleted rabies virus (RABV G) is a powerful tool for the analysis of neural circuits. Here, we demonstrate the utility of an anterograde RABV G variant for novel neuroanatomical approaches involving either bulk or sparse neuronal populations. This technology exploits the unique features of RABV G vectors, namely autonomous, rapid high-level expression of transgenes, and limited cytotoxicity. Our vector permits the unambiguous long-range and fine-scale tracing of the entire axonal arbor of individual neurons throughout the brain. Notably, this level of labeling can be achieved following infection with a single viral particle. The vector is effective over a range of ages (>14 months) aiding the studies of neurodegenerative disorders or aging, and infects numerous cell types in all brain regions tested. Lastly, it can also be readily combined with retrograde RABV G variants. Together with other modern technologies, this tool provides new possibilities for the investigation of the anatomy and physiology of neural circuits.




2013 | Front Neural Circuits   IF 5.1
Revealing the secrets of neuronal circuits with recombinant rabies virus technology.
Ginger M*, Haberl M*, Conzelmann KK, Schwarz MK, Frick A

Abstract:
An understanding of how the brain processes information requires knowledge of the architecture of its underlying neuronal circuits, as well as insights into the relationship between architecture and physiological function. A range of sophisticated tools is needed to acquire this knowledge, and recombinant rabies virus (RABV) is becoming an increasingly important part of this essential toolbox. RABV has been recognized for years for its properties as a synapse-specific trans-neuronal tracer. A novel genetically modified variant now enables the investigation of specific monosynaptic connections. This technology, in combination with other genetic, physiological, optical, and computational tools, has enormous potential for the visualization of neuronal circuits, and for monitoring and manipulating their activity. Here we will summarize the latest developments in this fast moving field and provide a perspective for the use of this technology for the dissection of neuronal circuit structure and function in the normal and diseased brain.




2013 | Front Neural Circuits   IF 5.1
Three-dimensional tracking and analysis of ion channel signals across dendritic arbors.
Ginger M, Broser P, Frick A

Abstract:
Most neuron types possess elaborate dendritic arbors that receive and integrate excitatory and inhibitory inputs from numerous other neurons to give rise to cell-type specific firing patterns. The computational properties of these dendrites are therefore crucial for neuronal information processing, and are strongly determined by the expression of many types of voltage-gated ion channels in their membrane. The dendritic distribution patterns of these ion channels are characteristic for each ion channel type, are dependent on the neuronal identity, and can be modified in a plastic or pathophysiological manner. We present a method that enables us to semi-automatically map and quantify in 3D the expression levels of specific ion channel types across the entire dendritic arbor. To achieve this, standard immunohistochemistry was combined with reconstruction and quantification procedures for the localization and relative distribution of ion channels with respect to dendritic morphology. This method can, in principle, be applied to any fluorescent signal, including fluorescently tagged membrane proteins, RNAs, or intracellular signaling molecules.




2012 | Nat Commun   IF 11.3
Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome.
Jung KM , Sepers M , Henstridge CM , Lassalle O , Neuhofer D , Martin H , Ginger M , Frick A , DiPatrizio NV , Mackie K , Katona I , Piomelli D , Manzoni OJ

Abstract:
Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain. Fragile X mental retardation protein deletion in mice enhances metabotropic glutamate receptor-5-dependent long-term depression in the hippocampus and cerebellum. Here we show that a distinct type of metabotropic glutamate receptor-5-dependent long-term depression at excitatory synapses of the ventral striatum and prefrontal cortex, which is mediated by the endocannabinoid 2-arachidonoyl-sn-glycerol, is absent in fragile X mental retardation protein-null mice. In these mutants, the macromolecular complex that links metabotropic glutamate receptor-5 to the 2-arachidonoyl-sn-glycerol-producing enzyme, diacylglycerol lipase-alpha (endocannabinoid signalosome), is disrupted and metabotropic glutamate receptor-5-dependent 2-arachidonoyl-sn-glycerol formation is compromised. These changes are accompanied by impaired endocannabinoid-dependent long-term depression. Pharmacological enhancement of 2-arachidonoyl-sn-glycerol signalling normalizes this synaptic defect and corrects behavioural abnormalities in fragile X mental retardation protein-deficient mice. The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.




15/02/2009 | J Physiol   IF 4.8
Synaptic ionotropic glutamate receptors and plasticity are developmentally altered in the CA1 field of Fmr1 knockout mice
Pilpel Y, Kolleker A, Berberich S, Ginger M, Frick A, Mientjes E, Oostra B A, Seeburg P H

Abstract:
Fragile X syndrome is one of the most common forms of mental retardation, yet little is known about the physiological mechanisms causing the disease. In this study, we probed the ionotropic glutamate receptor content in synapses of hippocampal CA1 pyramidal neurons in a mouse model for fragile X (Fmr1 KO2). We found that Fmr1 KO2 mice display a significantly lower AMPA to NMDA ratio than wild-type mice at 2 weeks of postnatal development but not at 6-7 weeks of age. This ratio difference at 2 weeks postnatally is caused by down-regulation of the AMPA and up-regulation of the NMDA receptor components. In correlation with these changes, the induction of NMDA receptor-dependent long-term potentiation following a low-frequency pairing protocol is increased in Fmr1 KO2 mice at this developmental stage but not later in maturation. We propose that ionotropic glutamate receptors, as well as potentiation, are altered at a critical time point for hippocampal network development, causing long-term changes. Associated learning and memory deficits would contribute to the fragile X mental retardation phenotype.




11/04/2006 | Proc Natl Acad Sci U S A   IF 9.6
A noncoding RNA is a potential marker of cell fate during mammary gland development
Ginger M R, Shore A N, Contreras A, Rijnkels M, Miller J, Gonzalez-Rimbau M F, Rosen J M

Abstract:
PINC is a large, alternatively spliced, developmentally regulated, noncoding RNA expressed in the regressed terminal ductal lobular unit-like structures of the parous mammary gland. Previous studies have shown that this population of cells possesses not only progenitor-like qualities (the ability to proliferate and repopulate a mammary gland) and the ability to survive developmentally programmed cell death but also the inhibition of carcinogen-induced proliferation. Here we report that PINC expression is temporally and spatially regulated in response to developmental stimuli in vivo and that PINC RNA is localized to distinct foci in either the nucleus or the cytoplasm in a cell-cycle-specific manner. Loss-of-function experiments suggest that PINC performs dual roles in cell survival and regulation of cell-cycle progression, suggesting that PINC may contribute to the developmentally mediated changes previously observed in the terminal ductal lobular unit-like structures of the parous gland. This is one of the first reports describing the functional properties of a large, developmentally regulated, mammalian, noncoding RNA.




12/2001 | Ann N Y Acad Sci   IF 2.7
Mechanisms of hormonal prevention of breast cancer.
Medina D, Sivaraman L, Hilsenbeck SG, Conneely O, Ginger M, Rosen J, Omalle BW

Abstract:
Reproductive history is a consistent risk factor for human breast cancer. Epidemiological studies have repeatedly demonstrated that early age of first pregnancy is a strong protective factor against breast cancer and provides a physiologically operative model to achieve a practical mode of prevention. In rodents, the effects of full-term pregnancy can be mimicked by a three-week exposure to low doses of estrogen and progesterone. Neither hormone alone is sufficient to induce protection. The cellular and molecular mechanisms that underlie hormone-induced refractoriness are largely unresolved. Our recent studies have demonstrated that an early cellular response that is altered in hormone-treated mammary cells is the initial proliferative burst induced by the chemical carcinogen methylnitrosourea. The decrease in proliferation is also accompanied by a decrease in the ability of estrogen receptor-positive cells to proliferate. RNA expression of several mammary cell-cycle-related genes is not altered in hormone-treated mice; however, immunohistochemical assays demonstrate that the protein level and nuclear compartmentalization of the p53 tumor suppressor gene are markedly upregulated as a consequence of hormone treatment. These results support the hypothesis that hormone stimulation, at a critical period in mammary development, results in cells with persistent changes in the intracellular regulatory loops governing proliferation and response to DNA damage. A corollary to this hypothesis is that the genes affected by estrogen and progesterone are independent of alveolar differentiation-specific genes. Suppressive subtractive hybridization-PCR methods have identified several genes that are differentially expressed as a consequence of prior estrogen and progesterone treatment. Future experiments are aimed at determining the mechanisms of hormone-induced upregulation of p53 protein expression as part of the overall goal of identifying and functionally characterizing the genes responsible for the refractory phenotype.