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  • 1
    Online Resource
    Online Resource
    Phosphoinositides Regulate P2X 4 ATP-Gated Channels through Direct Interactions
    Society for Neuroscience ; 2008
    In:  The Journal of Neuroscience Vol. 28, No. 48 ( 2008-11-26), p. 12938-12945
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 48 ( 2008-11-26), p. 12938-12945
    Abstract: P2X receptors are ATP-gated nonselective cation channels highly permeable to calcium that contribute to nociception and inflammatory responses. The P2X 4 subtype, upregulated in activated microglia, is thought to play a critical role in the development of tactile allodynia following peripheral nerve injury. Posttranslational regulation of P2X 4 function is crucial to the cellular mechanisms of neuropathic pain, however it remains poorly understood. Here, we show that the phosphoinositides PI(4,5)P 2 (PIP 2 ) and PI(3,4,5)P 3 (PIP 3 ), products of phosphorylation by wortmannin-sensitive phosphatidylinositol 4-kinases and phosphatidylinositol 3-kinases, can modulate the function of native and recombinant P2X 4 receptor channels. In BV-2 microglial cells, depleting the intracellular levels of PIP 2 and PIP 3 with wortmannin significantly decreased P2X 4 current amplitude and P2X 4 -mediated calcium entry measured in patch clamp recordings and ratiometric ion imaging, respectively. Wortmannin-induced depletion of phosphoinositides in Xenopus oocytes decreased the current amplitude of P2X 4 responses by converting ATP into a partial agonist. It also decreased their recovery from desensitization and affected their kinetics. Injection of phosphoinositides in wortmannin-treated oocytes reversed these effects and application of PIP 2 on excised inside-out macropatches rescued P2X 4 currents from rundown. Moreover, we report the direct interaction of phospholipids with the proximal C-terminal domain of P2X 4 subunit (Cys 360 –Val 375 ) using an in vitro binding assay. These results demonstrate novel regulatory roles of the major signaling phosphoinositides PIP 2 and PIP 3 on P2X 4 function through direct channel–lipid interactions.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3038-08.2008
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2008
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 2
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    Online Resource
    Loss of Quinone Reductase 2 Function Selectively Facilitates Learning Behaviors
    Society for Neuroscience ; 2010
    In:  The Journal of Neuroscience Vol. 30, No. 38 ( 2010-09-22), p. 12690-12700
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 38 ( 2010-09-22), p. 12690-12700
    Abstract: High levels of reactive oxygen species (ROS) are associated with deficits in learning and memory with age as well as in Alzheimer's disease. Using DNA microarray, we demonstrated the overexpression of quinone reductase 2 (QR2) in the hippocampus in two models of learning deficits, namely the aged memory impaired rats and the scopolamine-induced amnesia model. QR2 is a cytosolic flavoprotein that catalyzes the reduction of its substrate and enhances the production of damaging activated quinone and ROS. QR2-like immunostaining is enriched in cerebral structures associated with learning behaviors, such as the hippocampal formation and the temporofrontal cortex of rat, mouse, and human brains. In cultured rat embryonic hippocampal neurons, selective inhibitors of QR2, namely S26695 and S29434, protected against menadione-induced cell death by reversing its proapoptotic action. S26695 (8 mg/kg) also significantly inhibited scopolamine-induced amnesia. Interestingly, adult QR2 knock-out mice demonstrated enhanced learning abilities in various tasks, including Morris water maze, object recognition, and rotarod performance test. Other behaviors related to anxiety (elevated plus maze), depression (forced swim), and schizophrenia (prepulse inhibition) were not affected in QR2-deficient mice. Together, these data suggest a role for QR2 in cognitive behaviors with QR2 inhibitors possibly representing a novel therapeutic strategy toward the treatment of learning deficits especially observed in the aged brain.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2808-10.2010
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2010
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 3
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    Online Resource
    How Silent Is Silent Reading? Intracerebral Evidence for Top-Down Activation of Temporal Voice Areas during Reading
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 49 ( 2012-12-05), p. 17554-17562
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 49 ( 2012-12-05), p. 17554-17562
    Abstract: As you might experience it while reading this sentence, silent reading often involves an imagery speech component: we can hear our own “inner voice” pronouncing words mentally. Recent functional magnetic resonance imaging studies have associated that component with increased metabolic activity in the auditory cortex, including voice-selective areas. It remains to be determined, however, whether this activation arises automatically from early bottom-up visual inputs or whether it depends on late top-down control processes modulated by task demands. To answer this question, we collaborated with four epileptic human patients recorded with intracranial electrodes in the auditory cortex for therapeutic purposes, and measured high-frequency (50–150 Hz) “gamma” activity as a proxy of population level spiking activity. Temporal voice-selective areas (TVAs) were identified with an auditory localizer task and monitored as participants viewed words flashed on screen. We compared neural responses depending on whether words were attended or ignored and found a significant increase of neural activity in response to words, strongly enhanced by attention. In one of the patients, we could record that response at 800 ms in TVAs, but also at 700 ms in the primary auditory cortex and at 300 ms in the ventral occipital temporal cortex. Furthermore, single-trial analysis revealed a considerable jitter between activation peaks in visual and auditory cortices. Altogether, our results demonstrate that the multimodal mental experience of reading is in fact a heterogeneous complex of asynchronous neural responses, and that auditory and visual modalities often process distinct temporal frames of our environment at the same time.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2982-12.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 4
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    Online Resource
    Locking the Dimeric GABA B G-Protein-Coupled Receptor in Its Active State
    Society for Neuroscience ; 2004
    In:  The Journal of Neuroscience Vol. 24, No. 2 ( 2004-01-14), p. 370-377
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    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 24, No. 2 ( 2004-01-14), p. 370-377
    Abstract: G-protein-coupled receptors (GPCRs) play a major role in cell-cell communication in the CNS. These proteins oscillate between various inactive and active conformations, the latter being stabilized by agonists. Although mutations can lead to constitutive activity, most of these destabilize inactive conformations, and none lock the receptor in an active state. Moreover, GPCRs are known to form dimers, but the role of each protomer in the activation process remains unclear. Here, we show that the heterodimeric GPCR for the main inhibitory neurotransmitter, the GABA B receptor, can be locked in its active state by introducing two cysteines expected to form a disulphide bridge to maintain the binding domain of the GABA B1 subunit in a closed form. This constitutively active receptor cannot be inhibited by antagonists, but its normal functioning, activation by agonists, and inhibition by antagonists can be restored after reduction with dithiothreitol. These data show that the closed state of the binding domain of GABA B1 is sufficient to turn ON this heterodimeric receptor and illustrate for the first time that a GPCR can be locked in an active conformation.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3141-03.2004
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2004
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 5
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    N-Cadherin Prodomain Processing Regulates Synaptogenesis
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 18 ( 2012-05-02), p. 6323-6334
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    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 18 ( 2012-05-02), p. 6323-6334
    Abstract: Classical cadherins, which are adhesion molecules functioning at the CNS synapse, are synthesized as adhesively inactive precursor proteins in the endoplasmic reticulum (ER). Signal sequence and prodomain cleavage in the ER and Golgi apparatus, respectively, activates their adhesive properties. Here, we provide the first evidence for sorting of nonadhesive precursor N-cadherin (ProN) to the neuronal surface, where it coexists with adhesively competent mature N-cadherin (N-cad), generating a spectrum of adhesive strengths. In cultured hippocampal neurons, a high ProN/N-cad ratio downregulates synapse formation. Neurons expressing genetically engineered uncleavable ProN make markedly fewer synapses. The synapse number can be rescued to normality by depleting surface ProN levels through prodomain cleavage by an exogenous protease. Finally, prodomain processing is developmentally regulated in the rat hippocampus. We conclude that it is the ProN/N-cad ratio and not mature N-cad alone that is critical for regulation of adhesion during synaptogenesis.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0916-12.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 6
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    Online Resource
    Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography Imaging
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 32 ( 2012-08-08), p. 10809-10818
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 32 ( 2012-08-08), p. 10809-10818
    Abstract: Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo . We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPO radioligands, [ 18 F]DPA-714 [ N,N -diethyl-2-(2-(4-(2-[ 18 F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide] and [ 11 C]SSR180575 (7-chloro- N , N -dimethyl-5-[ 11 C]methyl-4-oxo-3-phenyl-3,5-dihydro-4 H -pyridazino[4,5- b ]indole-1-acetamide), showed a significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 [ N -methyl- N -(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide]. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1487-12.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
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  • 7
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    Online Resource
    Transient Suppression of Broadband Gamma Power in the Default-Mode Network Is Correlated with Task Complexity and Subject Performance
    Society for Neuroscience ; 2011
    In:  The Journal of Neuroscience Vol. 31, No. 41 ( 2011-10-12), p. 14521-14530
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    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 41 ( 2011-10-12), p. 14521-14530
    Abstract: Task performance is associated with increased brain metabolism but also with prominent deactivation in specific brain structures known as the default-mode network (DMN). The role of DMN deactivation remains enigmatic in part because its electrophysiological correlates, temporal dynamics, and link to behavior are poorly understood. Using extensive depth electrode recordings in humans, we provide first electrophysiological evidence for a direct correlation between the dynamics of power decreases in the DMN and individual subject behavior. We found that all DMN areas displayed transient suppressions of broadband gamma (60–140 Hz) power during performance of a visual search task and, critically, we show for the first time that the millisecond range duration and extent of the transient gamma suppressions are correlated with task complexity and subject performance. In addition, trial-by-trial correlations revealed that spatially distributed gamma power increases and decreases formed distinct anticorrelated large-scale networks. Beyond unraveling the electrophysiological basis of DMN dynamics, our results suggest that, rather than indicating a mere switch to a global exteroceptive mode, DMN deactivation encodes the extent and efficiency of our engagement with the external world. Furthermore, our findings reveal a pivotal role for broadband gamma modulations in the interplay between task-positive and task-negative networks mediating efficient goal-directed behavior and facilitate our understanding of the relationship between electrophysiology and neuroimaging studies of intrinsic brain networks.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2483-11.2011
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2011
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 8
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    Online Resource
    GABA B Receptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation
    Society for Neuroscience ; 2010
    In:  The Journal of Neuroscience Vol. 30, No. 2 ( 2010-01-13), p. 749-759
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    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 2 ( 2010-01-13), p. 749-759
    Abstract: The G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) play key roles in cell–cell communication. Several studies revealed important synergisms between these two types of receptors, with some of the actions of either receptor being mediated through transactivation of the other. Among the large GPCR family, GABA B receptor is activated by the neurotransmitter GABA, and is expressed in most neurons where it mediates slow and prolonged inhibition of synaptic transmission. Here we show that this receptor is involved in the regulation of life and death decisions of cerebellar granule neurons (CGNs). We show that specific activation of GABA B receptor can protect neurons from apoptosis through a mechanism that involves transactivation of the IGF-1 receptor (IGF-1R). Further work demonstrated that this cross talk was dependent on G i/o -protein, PLC, cytosolic Ca 2+ , and FAK1 but independent of PKC, while IGF-1R-induced signaling involved Src kinase, PI3 kinase, and Akt activation. These results reveal a new function for this important GPCR and further highlight the importance of functional cross-talk networks between GPCRs and RTKs. Our results reveal GABA B receptor as a potential drug target for the treatment of neurodegenerative disorders.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2343-09.2010
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2010
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 9
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    Online Resource
    Efficient “Pop-Out” Visual Search Elicits Sustained Broadband Gamma Activity in the Dorsal Attention Network
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 10 ( 2012-03-07), p. 3414-3421
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    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 10 ( 2012-03-07), p. 3414-3421
    Abstract: An object that differs markedly from its surrounding—for example, a red cherry among green leaves—seems to pop out effortlessly in our visual experience. The rapid detection of salient targets, independently of the number of other items in the scene, is thought to be mediated by efficient search brain mechanisms. It is not clear, however, whether efficient search is actually an “effortless” bottom-up process or whether it also involves regions of the prefrontal cortex generally associated with top-down sustained attention. We addressed this question with intracranial EEG (iEEG) recordings designed to identify brain regions underlying a classic visual search task and correlate neural activity with target detection latencies on a trial-by-trial basis with high temporal precision recordings of these regions in epileptic patients. The spatio-temporal dynamics of single-trial spectral analysis of iEEG recordings revealed sustained energy increases in a broad gamma band (50–150 Hz) throughout the duration of the search process in the entire dorsal attention network both in efficient and inefficient search conditions. By contrast to extensive theoretical and experimental indications that efficient search relies exclusively on transient bottom-up processes in visual areas, we found that efficient search is mediated by sustained gamma activity in the dorsal lateral prefrontal cortex and the anterior cingulate cortex, alongside the superior parietal cortex and the frontal eye field. Our findings support the hypothesis that active visual search systematically involves the frontal-parietal attention network and therefore, executive attention resources, regardless of target saliency.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.6048-11.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 10
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    Online Resource
    Long-Distance Amplitude Correlations in the High Gamma Band Reveal Segregation and Integration within the Reading Network
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 19 ( 2012-05-09), p. 6421-6434
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    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 19 ( 2012-05-09), p. 6421-6434
    Abstract: Reading sentences involves a distributed network of brain regions acting in concert surrounding the left sylvian fissure. The mechanisms of neural communication underlying the extraction and integration of verbal information across subcomponents of this reading network are still largely unknown. We recorded intracranial EEG activity in 12 epileptic human patients performing natural sentence reading and analyzed long-range corticocortical interactions between local neural activations. During a simple task contrasting semantic, phonological, and purely visual processes, we found process-specific neural activity elicited at the single-trial level, characterized by energy increases in a broad gamma band (40–150 Hz). Correlation analysis between task-induced gamma-band activations revealed a selective fragmentation of the network into specialized subnetworks supporting sentence-level semantic analysis and phonological processing. We extend the implications of our results beyond reading, to propose that gamma-band amplitude correlations might constitute a fundamental mechanism for large-scale neural integration during high-level cognition.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.4363-11.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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