Neuroscience_topics
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Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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De nouveaux résultats soulignent l'importance des gènes synaptiques dans l'autisme

De nouveaux résultats soulignent l'importance des gènes synaptiques dans l'autisme | Neuroscience_topics | Scoop.it

L'autisme, nommé grande cause nationale, sera un sujet d'actualité en France pendant toute l'année 2012. Paradoxalement ce syndrome, et surtout ses origines, restent mal connus. Une étude, publiée le 9 février 2012 dans Public Library of Science - Genetics, démontre que des mutations génétiques perturbant la communication entre les neurones seraient directement impliquées dans la maladie. Ces nouveaux résultats confirment l'origine neurobiologique des troubles du spectre autistique. Ils sont le fruit d'une collaboration entre des chercheurs de l'Institut Pasteur, du CNRS, de l'Inserm, et de l'AP-HP, avec l'université Paris Diderot, l'hôpital Robert Debré (AP-HP), le Centre Gillberg de Neuropsychiatrie (Suède), l'université d'Ulm (Allemagne), le Centre National de Génotypage du CEA, et la Fondation FondaMental.

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Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export

Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export | Neuroscience_topics | Scoop.it

This is a new study shows that mice lacking tau develop parkinsonism because of intracellular iron accumulation that results in degeneration of dopamine neurons. Tau deficiency seems to impair ferroportin iron export by retention of the amyloid precursor protein, a neuronal ferroxidase partner, inside the endoplasmic reticulum. (Nature Medecine, 18, 291–295,2012) 

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Subcellular calcium dynamics in a whole-cell model of an atrial myocyte

Subcellular calcium dynamics in a whole-cell model of an atrial myocyte | Neuroscience_topics | Scoop.it

In this study, we present an innovative mathematical modeling approach that allows detailed characterization of Ca2+ movement within the three-dimensional volume of an atrial myocyte. Essential aspects of the model are the geometrically realistic representation of Ca2+ release sites and physiological Ca2+ flux parameters, coupled with a computationally inexpensive framework. By translating nonlinear Ca2+ excitability into threshold dynamics, we avoid the computationally demanding time stepping of the partial differential equations that are often used to model Ca2+ transport. Our approach successfully reproduces key features of atrial myocyte Ca2+ signaling observed using confocal imaging. In particular, the model displays the centripetal Ca2+ waves that occur within atrial myocytes during excitation–contraction coupling, and the effect of positive inotropic stimulation on the spatial profile of the Ca2+ signals. Beyond this validation of the model, our simulation reveals unexpected observations about the spread of Ca2+ within an atrial myocyte. In particular, the model describes the movement of Ca2+ between ryanodine receptor clusters within a specific z disk of an atrial myocyte. Furthermore, we demonstrate that altering the strength of Ca2+ release, ryanodine receptor refractoriness, the magnitude of initiating stimulus, or the introduction of stochastic Ca2+ channel activity can cause the nucleation of proarrhythmic traveling Ca2+ waves. The model provides clinically relevant insights into the initiation and propagation of subcellular Ca2+ signals that are currently beyond the scope of imaging technology.

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Cracks in the Plaques: Mysteries of Alzheimer's Slowly Yielding to New Research

Cracks in the Plaques: Mysteries of Alzheimer's Slowly Yielding to New Research | Neuroscience_topics | Scoop.it

Science is bringing some understanding of the heritability, prevalence, and inner workings of one of the most devastating diseases (Scientific American)

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Structure of a KirBac potassium channel with an open bundle crossing indicates a mechanism of channel gating

Structure of a KirBac potassium channel with an open bundle crossing indicates a mechanism of channel gating | Neuroscience_topics | Scoop.it

KirBac channels are prokaryotic homologs of mammalian inwardly rectifying (Kir) potassium channels, and recent crystal structures of both Kir and KirBac channels have provided major insight into their unique structural architecture. (...) In this study, we engineered the inner pore-lining helix (TM2) of KirBac3.1 to trap the bundle crossing in an apparently open conformation and determined the crystal structure of this mutant channel to 3.05 Å resolution. Contrary to previous speculation, this new structure suggests a mechanistic model in which rotational 'twist' of the cytoplasmic domain is coupled to opening of the bundle-crossing gate through a network of inter- and intrasubunit interactions that involve the TM2 C-linker, slide helix, G-loop and the CD loop.

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Cofilin Aggregation Blocks Intracellular Trafficking and Induces Synaptic Loss in Hippocampal Neurons

Cofilin Aggregation Blocks Intracellular Trafficking and Induces Synaptic Loss in Hippocampal Neurons | Neuroscience_topics | Scoop.it

Cofilin is an actin-binding protein and a major actin depolymerization factor in the central nervous system (CNS). Cofilin-actin aggregates are associated with neurodegenerative disorders, but how cofilin-actin aggregation induces pathological effects in the CNS remains unclear. Here, we demonstrated that cofilin rods disrupted dendritic microtubule integrity in rat hippocampal cultures. Long term time-lapse imaging revealed that cofilin rods block intracellular trafficking of both mitochondria and early endosomes. Importantly, cofilin rod formation induced a significant loss of SV2 and PSD-95 puncta as well as dendritic spines. Cofilin rods also impaired local glutamate receptor responses. We discovered an inverse relationship between the number of synaptic events and the accumulation of cofilin rods in dendrites. We also detected cofilin rods in aging rat brains in vivo. These results suggest that cofilin aggregation may contribute to neurodegeneration and brain aging by blocking intracellular trafficking and inducing synaptic loss.

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Patients help bring the study of Alzheimer’s to the dish

Patients help bring the study of Alzheimer’s to the dish | Neuroscience_topics | Scoop.it

Lawrence Goldstein and colleagues go right to the source and purify skin fibroblasts from AD patients with the intent to turn them into neurons for study. The authors took skin cells from 2 patients with familial AD (the genetically-inherited version), 2 patients with sporadic AD and 2 control patients. These cells were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently directed to form neurons. Neurons were purified and allowed to mature and then were tested to determine whether the resulting cultures presented signs of neuronal maturity. Once satisfied with these critical assessments, the authors moved towards documenting abnormalities in the diseased cells, while also observing disruptions in specific organelles. One aspect that particularly makes these culture models attractive is the ability to easily manipulate the cells pharmacologically, with the authors demonstrating that treatment of diseased neurons with β-secretase inhibitors reduced the levels of some pathophysiological markers. In short, despite only living in a dish for a few weeks, these iPSC lines could still recapitulate disease phenotypes that take decades to develop. And perhaps most importantly, these results represented one of the first possible models for sporadic AD.

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Primed for Addiction?

Primed for Addiction? | Neuroscience_topics | Scoop.it

Families hand down many things from one generation to the next—and addiction can be one of them. A child of drug-addicted parents is eight times more likely to become an addict than a child growing up in a drug-free home. But genes aren't everything. Even in families whose very brains seem primed for addiction, some children still go on to lead productive lives free of drugs, according to new research. (ScienceNOW)

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Prion protein at the crossroads of physiology and disease (review)

Prion protein at the crossroads of physiology and disease (review) | Neuroscience_topics | Scoop.it

[Review] The presence of the cellular prion protein (PrPC) on the cell surface is critical for the neurotoxicity of prions. Although several biological activities have been attributed to PrPC, a definitive demonstration of its physiological function remains elusive. In this review, we discuss some of the proposed functions of PrPC, focusing on recently suggested roles in cell adhesion, regulation of ionic currents at the cell membrane and neuroprotection. We also discuss recent evidence supporting the idea that PrPC may function as a receptor for soluble oligomers of the amyloid β peptide and possibly other toxic protein aggregates. These data suggest surprising new connections between the physiological function of PrPC and its role in neurodegenerative diseases beyond those caused by prions.

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Quand la sérotonine tombe sur un os

Quand la sérotonine tombe sur un os | Neuroscience_topics | Scoop.it

La sérotonine, un neurotransmetteur cérébral bien connu, est produite localement dans un site inattendu : le tissu osseux. C’est ce que viennent de montrer les chercheurs de l’Unité mixte de recherche 606 "Os et Articulation" (Inserm/Université Paris Diderot) associés au laboratoire de biochimie de l’hôpital Lariboisière et au laboratoire "Cytokines, hématopoïèse et réponse immune" (CNRS/Université Paris Descartes)à l’hôpital Necker à Paris. Cette sérotonine locale favoriserait la dégradation du tissu osseux. Ces résultats publiés cette semaine dans les PNAS suggèrent que des médicaments modulant les effets de la sérotonine, comme les antidépresseurs ou les antimigraineux, pourraient modifier dans un sens ou dans l’autre l’équilibre délicat entre formation et dégradation des os dans l’organisme.

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Ca2+ signaling amplification by oligomerization of L-type Cav1.2 channels

Ca2+ signaling amplification by oligomerization of L-type Cav1.2 channels | Neuroscience_topics | Scoop.it

Ca2+ influx via L-type Cav1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the Ca2+ signals produced by the opening of these channels is a hallmark of many intracellular signaling cascades, including excitation-contraction coupling in heart. Using optogenetic approaches, we discovered that Cav1.2 channels form clusters of varied sizes in ventricular myocytes. Physical interaction between these channels via their C-tails renders them capable of coordinating their gating, thereby amplifying Ca2+ influx and excitation-contraction coupling. Light-induced fusion of WT Cav1.2 channels with Cav1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Cav1.2-TS) increased Ca2+ currents, diastolic and systolic Ca2+ levels, contractility and the frequency of arrhythmogenic Ca2+ fluctuations in ventricular myocytes. Our data indicate that these changes in Ca2+ signaling resulted from Cav1.2-TS increasing the activity of adjoining WT Cav1.2 channels. Collectively, these data support the concept that oligomerization of Cav1.2 channels via their C termini can result in the amplification of Ca2+ influx into excitable cells.

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[Review] Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

[Review] Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy | Neuroscience_topics | Scoop.it

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders. (Nature Reviews Drug Discovery, 11, 141-168, February 2012)

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Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-d-aspartate receptors

Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-d-aspartate receptors | Neuroscience_topics | Scoop.it

N-methyl-D-aspartate receptors (NMDARs) mediate critical CNS functions, whereas excessive activity contributes to neuronal damage. At physiological glycine concentrations, NMDAR currents recorded from cultured rodent hippocampal neurons exhibited strong desensitization in the continued presence of NMDA, thus protecting neurons from calcium overload. (...) We propose a physiological role for PrPC, one that limits excessive NMDAR activity that might otherwise promote neuronal damage. In addition, we provide a unifying molecular mechanism whereby toxic species of Aβ1–42 might mediate neuronal and synaptic injury, at least in part, by disrupting the normal copper-mediated, PrPC-dependent inhibition of excessive activity of this highly calcium-permeable glutamate receptor. 

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Natural Resistance [and ion channels]

Avermectins are the most widely used class of anthelmintic drugs, both as pesticides and as treatments for nematode-borne diseases, with the evolution of resistance presenting a major global health and agricultural problem. Ghosh et al. (see the Perspective by Wolstenholme) observed resistance to avermectin in the model nematode Caenorhabditis elegans that varies among isolates. This resistance is caused by a naturally occurring four–amino acid deletion in the ligand-binding domain of a glutamate-gated chloride channel. This variant also conferred resistance to the avermectin-producing ubiquitous soil bacterium Streptomyces zitilis. Many nematodes spend at least part of their life cycle in soil, which may explain avermectin resistance among nematode species. (Science)

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Binding Modes of μ-Conotoxin to the Bacterial Sodium Channel (NaVAb)

Binding Modes of μ-Conotoxin to the Bacterial Sodium Channel (NaVAb) | Neuroscience_topics | Scoop.it

Polypeptide toxins isolated from the venom of cone snails, known as μ-conotoxins, block voltage-gated sodium channels by physically occluding the ion-conducting pathway. Using molecular dynamics, we show that one subtype of μ-conotoxins, PIIIA, effectively blocks the bacterial voltage-gated sodium channel NaVAb, whose crystal structure has recently been elucidated. The spherically shaped toxin, carrying a net charge of +6 e with six basic residues protruding from its surface, is attracted by the negatively charged residues on the vestibular wall and the selectivity filter of the channel. The side chain of each of these six arginine and lysine residues can wedge into the selectivity filter, whereas the side chains of other basic residues form electrostatic complexes with two acidic residues on the channel. We construct the profile of potential of mean force for the unbinding of PIIIA from the channel, and predict that PIIIA blocks the bacterial sodium channel with subnanomolar affinity.  (Biophysical Journal)

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NaV1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

NaV1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms | Neuroscience_topics | Scoop.it

NaV1.1 is the primary voltage-gated Na+ channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that NaV1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a+/−), which encodes the pore-forming α-subunit of the NaV1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a+/− mice have exaggerated light-induced negative-masking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a+/− mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a+/− mice, and this communication is barely detectable in the homozygous gene KO (Scn1a−/−). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of NaV1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na+ channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of NaV1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients. (PNAS)

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Why Two New Studies Represent an Important Breakthrough in Alzheimer’s Disease Research

Why Two New Studies Represent an Important Breakthrough in Alzheimer’s Disease Research | Neuroscience_topics | Scoop.it

Two different research groups have independently made the same important discoveries on how Alzheimer’s disease spreads in the brain. The groups’ findings have the potential to give us a much more sophisticated understanding of what goes wrong in Alzheimer’s disease and, more importantly, what can be done to prevent or repair damage in the brain. (AHAF)

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N-Methyl-d-aspartate Receptor Mechanosensitivity Is Governed by C Terminus of NR2B Subunit

N-Methyl-d-aspartate Receptor Mechanosensitivity Is Governed by C Terminus of NR2B Subunit | Neuroscience_topics | Scoop.it

N-Methyl-D-aspartate receptors (NMDARs), critical mediators of both physiologic and pathologic neurological signaling, have previously been shown to be sensitive to mechanical stretch through the loss of its native Mg2+ block. However, the regulation of this mechanosensitivity has yet to be further explored. Furthermore, as it has become apparent that NMDAR-mediated signaling is dependent on specific NMDAR subtypes, as governed by the identity of the NR2 subunit, a crucial unanswered question is the role of subunit composition in observed NMDAR mechanosensitivity. Here, we used a recombinant system to assess the mechanosensitivity of specific subtypes and demonstrate that the mechanosensitive property is uniquely governed by the NR2B subunit. NR1/NR2B NMDARs displayed significant stretch sensitivity, whereas NR1/NR2A NMDARs did not respond to stretch. Furthermore, NR2B mechanosensitivity was regulated by PKC activity, because PKC inhibition reduced stretch responses in transfected HEK 293 cells and primary cortical neurons. Finally, using NR2B point mutations, we identified a PKC phosphorylation site, Ser-1323 on NR2B, as a unique critical regulator of stretch sensitivity. These data suggest that the selective mechanosensitivity of NR2B can significantly impact neuronal response to traumatic brain injury and illustrate that the mechanical tone of the neuron can be dynamically regulated by PKC activity.

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Domain coupling in GPCRs: the engine for induced conformational changes

Domain coupling in GPCRs: the engine for induced conformational changes | Neuroscience_topics | Scoop.it

[Review] Recent solved structures of G protein-coupled receptors (GPCRs) provide insights into variation of the structure and molecular mechanisms of GPCR activation. In this review, we provide evidence for the emerging paradigm of domain coupling facilitated by intrinsic disorder of the ligand-free state in GPCRs. The structure–function and dynamic studies suggest that ligand-bound GPCRs exhibit multiple active conformations in initiating cellular signals. Long-range intramolecular and intermolecular interactions at distant sites on the same receptor are crucial factors that modulate signaling function of GPCRs. Positive or negative coupling between the extracellular, the transmembrane and the intracellular domains facilitates cooperativity of activating ‘switches’ as requirements for the functional plasticity of GPCRs. Awareness that allosteric ligands robustly affect domain coupling provides a novel mechanistic basis for rational drug development, small molecule antagonism and GPCR regulation by classical as well as nonclassical modes.

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Psychiatric disorders: Why two is better than one

Psychiatric disorders: Why two is better than one | Neuroscience_topics | Scoop.it

Many depression and anxiety disorders are most effectively treated with a combination of psychotherapy and antidepressant drugs. The biological basis for this observation is not well understood, but Castrén and colleagues now show that the antidepressant fluoxetine increases synaptic plasticity in the amygdala and thereby facilitates long-lasting fear extinction. (Nature Neuroscience)

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Postsynaptic signaling during plasticity of dendritic spines (review)

Postsynaptic signaling during plasticity of dendritic spines (review) | Neuroscience_topics | Scoop.it

{Review)Dendritic spines, small bulbous postsynaptic compartments emanating from neuronal dendrites, have been thought to serve as basic units of memory storage. Despite their small size (∼0.1 femtoliter), thousands of species of proteins exist in the spine, including receptors, channels, scaffolding proteins and signaling enzymes. Biochemical signaling mediated by these molecules leads to morphological and functional plasticity of dendritic spines, and ultimately learning and memory in the brain. Here, we review new insights into the mechanisms underlying spine plasticity brought about by recent advances in imaging techniques to monitor molecular events in single dendritic spines. The activity of each protein displays a specific spatiotemporal pattern, coordinating downstream events at different microdomains to change the function and morphology of dendritic spines. (TiNS)

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The Neuroscience of Looking on the Bright Side

The Neuroscience of Looking on the Bright Side | Neuroscience_topics | Scoop.it

Scientists use "prediction errors" to understand the brain's natural optimism (Scientific American)

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Le blog des livres : La recherche biomédicale en danger - La Recherche

Professeur émérite et ancien vice-président de l'université de Paris-5, ancien doyen de la faculté de médecine Necker et président de l'institut Necker, Philippe Even est un habitué des rayons de librairies et des cris d’arlarme.
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Mind-reading program translates brain activity into words

Mind-reading program translates brain activity into words | Neuroscience_topics | Scoop.it

The research paves the way for brain implants that would translate the thoughts of people who have lost power of speech (Mind-reading program translates brain activity into words

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3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders

3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders | Neuroscience_topics | Scoop.it

Emerging evidence suggests that the pathogenesis of depressive disorders (DDs) is associated with neuronal abnormalities in brain microtubule function, including changes in α-tubulin isoforms. Currently available antidepressant drugs may act by rescuing these alterations, but only after long-term treatment explaining their delayed therapeutic efficacy. (...) In the rat isolation-rearing model of depression, administration of MAP4343 showed more rapid and more persistent efficacy compared with fluoxetine in recovering “depressive-like” behaviors. These effects were accompanied by modifications of α-tubulin isoforms in the hippocampus, amygdala, and prefrontal cortex. Our findings suggest the potential therapeutic use of MAP4343 for the treatment of DDs, based on a unique mechanism of action.

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