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  • Society for Neuroscience  (14)
  • Linguistics  (14)
  • 1
    Online Resource
    Online Resource
    Identification of Protein Tyrosine Phosphatase Receptor Type O (PTPRO) as a Synaptic Adhesion Molecule that Promotes Synapse Formation
    Society for Neuroscience ; 2017
    In:  The Journal of Neuroscience Vol. 37, No. 41 ( 2017-10-11), p. 9828-9843
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 37, No. 41 ( 2017-10-11), p. 9828-9843
    Abstract: The proper formation of synapses—specialized unitary structures formed between two neurons—is critical to mediating information flow in the brain. Synaptic cell adhesion molecules (CAMs) are thought to participate in the initiation of the synapse formation process. However, in vivo functional analysis demonstrates that most well known synaptic CAMs regulate synaptic maturation and plasticity rather than synapse formation, suggesting that either CAMs work synergistically in the process of forming synapses or more CAMs remain to be found. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters in co-cultures of human embryonic kidney 293 cells and hippocampal neurons cultured from newborn mice regardless of gender. PTPRO was enriched in the mouse brain and localized to postsynaptic sites at excitatory synapses. The overexpression of PTPRO in cultured hippocampal neurons increased the number of synapses and the frequency of miniature EPSCs (mEPSCs). The knock-down (KD) of PTPRO expression in cultured neurons by short hairpin RNA (shRNA) reduced the number of synapses and the frequencies of the mEPSCs. The effects of shRNA KD were rescued by expressing either full-length PTPRO or a truncated PTPRO lacking the cytoplasmic domain. Consistent with these results, the N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in the co-culture assay. Our data show that PTPRO is a synaptic CAM that serves as a potent initiator of the formation of excitatory synapses. SIGNIFICANCE STATEMENT The formation of synapses is critical for the brain to execute its function and synaptic cell adhesion molecules (CAMs) play essential roles in initiating the formation of synapses. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters. Using loss-of-function and gain-of-function approaches, we show that PTPRO promotes the formation of excitatory synapses. The N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in cultured hippocampal neurons and the co-culture assay. Together, our data show that PTPRO is a synaptic CAM that serves as a potent initiator of synapse formation.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0729-17.2017
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2017
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  • 2
    Online Resource
    Online Resource
    Molecular Mechanism of Constitutive Endocytosis of Acid-Sensing Ion Channel 1a and Its Protective Function in Acidosis-Induced Neuronal Death
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 16 ( 2013-04-17), p. 7066-7078
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 16 ( 2013-04-17), p. 7066-7078
    Abstract: Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the peripheral and CNSs, which critically contribute to a variety of pathophysiological conditions that involve tissue acidosis, such as ischemic stroke and epileptic seizures. However, the trafficking mechanisms of ASICs and the related proteins remain largely unknown. Here, we demonstrate that ASIC1a, the main ASIC subunit in the brain, undergoes constitutive endocytosis in a clathrin- and dynamin-dependent manner in both mouse cortical neurons and heterologous cell cultures. The endocytosis of ASIC1a was inhibited by either the small molecular inhibitor tyrphostin A23 or knockdown of the core subunit of adaptor protein 2 (AP2) μ2 using RNA interference, supporting a clathrin-dependent endocytosis of ASIC1a. In addition, the internalization of ASIC1a was blocked by dominant-negative dynamin1 mutation K44A and the small molecular inhibitor dynasore, suggesting that it is also dynamin-dependent. We show that the membrane-proximal residues 465 LCRRG 469 at the cytoplasmic C terminus of ASIC1a are critical for interaction with the endogenous adaptor protein complex and inhibition of ASIC1a internalization strongly exacerbated acidosis-induced death of cortical neurons from wild-type but not ASIC1a knock-out mice. Together, these results reveal the molecular mechanism of ASIC1a internalization and suggest the importance of endocytic pathway in functional regulation of ASIC1a channels as well as neuronal damages mediated by these channels during neurodegeneration.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5206-12.2013
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
    detail.hit.zdb_id: 1475274-8
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  • 3
    Online Resource
    Online Resource
    Synaptic Metaplasticity through NMDA Receptor Lateral Diffusion
    Society for Neuroscience ; 2008
    In:  The Journal of Neuroscience Vol. 28, No. 12 ( 2008-03-19), p. 3060-3070
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 12 ( 2008-03-19), p. 3060-3070
    Abstract: Lateral diffusion of glutamate receptors was proposed as a mechanism for regulating receptor numbers at synapses and affecting synaptic functions, especially the efficiency of synaptic transmission. However, a direct link between receptor lateral diffusion and change in synaptic function has not yet been established. In the present study, we demonstrated NMDA receptor (NMDAR) lateral diffusion in CA1 neurons in hippocampal slices by detecting considerable recovery of spontaneous or evoked EPSCs from the block of (+)-MK-801 [(+)-5-methyl-10,11-dihydro-5 H -dibenzo [a,d] cyclohepten-5,10-imine maleate] , an irreversible NMDAR open-channel blocker. We observed changes on both the number and the composition of synaptic NMDAR on recovery. More importantly, after the recovery, long-term potentiation (LTP)-producing protocol induced only LTD (long-term depression) instead of LTP. In contrast, a complete recovery from competitive NMDAR blocker d,l -AP-5 was observed without subsequent changes on synaptic plasticity. Our data suggest a revised model of NMDAR trafficking wherein extrasynaptic NMDARs, mostly NR1/NR2B receptors, move laterally into synaptic sites, resulting in altered rule of synaptic modification. Thus, CA1 synapses exhibit a novel form of metaplasticity in which the direction of synaptic modification can be reverted through subtype-specific lateral diffusion of NMDA receptors.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5450-07.2008
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2008
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  • 4
    Online Resource
    Online Resource
    Mutational Analysis Establishes a Critical Role for the N Terminus of Fragile X Mental Retardation Protein FMRP
    Society for Neuroscience ; 2008
    In:  The Journal of Neuroscience Vol. 28, No. 12 ( 2008-03-19), p. 3221-3226
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 12 ( 2008-03-19), p. 3221-3226
    Abstract: Fragile X syndrome is the most common form of heritable mental retardation caused by the loss of function of the fragile X mental retardation protein FMRP. FMRP is a multidomain, RNA-binding protein involved in RNA transport and/or translational regulation. However, the binding specificity between FMRP and its various partners including interacting proteins and mRNA targets is essentially unknown. Previous work demonstrated that dFMRP, the Drosophila homolog of human FMRP, is structurally and functionally conserved with its mammalian counterparts. Here, we perform a forward genetic screen and isolate 26 missense mutations at 13 amino acid residues in the dFMRP coding dfmr1 . Interestingly, all missense mutations identified affect highly conserved residues in the N terminal of dFMRP. Loss- and gain-of-function analyses reveal altered axonal and synaptic elaborations in mutants. Yeast two-hybrid assays and in vivo analyses of interaction with CYFIP (cytoplasmic FMR1 interacting protein) in the nervous system demonstrate that some of the mutations disrupt specific protein–protein interactions. Thus, our mutational analyses establish that the N terminus of FMRP is critical for its neuronal function.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5528-07.2008
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2008
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  • 5
    Online Resource
    Online Resource
    Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory
    Society for Neuroscience ; 2015
    In:  The Journal of Neuroscience Vol. 35, No. 13 ( 2015-04-01), p. 5097-5108
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 35, No. 13 ( 2015-04-01), p. 5097-5108
    Abstract: Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis -regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 ( Mll1 ), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1 -deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at 〈 50 loci, including the homeodomain transcription factor Meis2 . Small RNA-mediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1 -regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3004-14.2015
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2015
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  • 6
    Online Resource
    Online Resource
    N -Acetyl-Serotonin Offers Neuroprotection through Inhibiting Mitochondrial Death Pathways and Autophagic Activation in Experimental Models of Ischemic Injury
    Society for Neuroscience ; 2014
    In:  The Journal of Neuroscience Vol. 34, No. 8 ( 2014-02-19), p. 2967-2978
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 8 ( 2014-02-19), p. 2967-2978
    Abstract: N -acetylserotonin (NAS) is an immediate precursor of melatonin, which we have reported is neuroprotective against ischemic injury. Here we test whether NAS is a potential neuroprotective agent in experimental models of ischemic injury. We demonstrate that NAS inhibits cell death induced by oxygen–glucose deprivation or H 2 O 2 in primary cerebrocortical neurons and primary hippocampal neurons in vitro , and organotypic hippocampal slice cultures ex vivo and reduces hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of cerebral ischemia in vivo . We find that NAS is neuroprotective by inhibiting the mitochondrial cell death pathway and the autophagic cell death pathway. The neuroprotective effects of NAS may result from the influence of mitochondrial permeability transition pore opening, mitochondrial fragmentation, and inhibition of the subsequent release of apoptogenic factors cytochrome c , Smac, and apoptosis-inducing factor from mitochondria to cytoplasm, and activation of caspase-3, -9, as well as the suppression of the activation of autophagy under stress conditions by increasing LC3-II and Beclin-1 levels and decreasing p62 level. However, NAS, unlike melatonin, does not provide neuroprotection through the activation of melatonin receptor 1A. We demonstrate that NAS reaches the brain subsequent to intraperitoneal injection using liquid chromatography/mass spectrometry analysis. Given that it occurs naturally and has low toxicity, NAS, like melatonin, has potential as a novel therapy for ischemic injury.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1948-13.2014
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2014
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  • 7
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    Online Resource
    SECISBP2L-Mediated Selenoprotein Synthesis Is Essential for Autonomous Regulation of Oligodendrocyte Differentiation
    Society for Neuroscience ; 2022
    In:  The Journal of Neuroscience Vol. 42, No. 30 ( 2022-07-27), p. 5860-5869
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 42, No. 30 ( 2022-07-27), p. 5860-5869
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1523/JNEUROSCI.2141-21.2022
    DOI: 10.1523/JNEUROSCI.2141-21.2022.f8-1
    DOI: 10.1523/JNEUROSCI.2141-21.2022.video.1
    DOI: 10.1523/JNEUROSCI.2141-21.2022.video.2
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2022
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  • 8
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    Online Resource
    USP1/UAF1-Stabilized METTL3 Promotes Reactive Astrogliosis and Improves Functional Recovery after Spinal Cord Injury through m 6 A Modification of YAP1 mRNA
    Society for Neuroscience ; 2023
    In:  The Journal of Neuroscience Vol. 43, No. 9 ( 2023-03-01), p. 1456-1474
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 43, No. 9 ( 2023-03-01), p. 1456-1474
    Abstract: RNA N 6 -methyladenosine (m 6 A) modification is involved in diverse biological processes. However, its role in spinal cord injury (SCI) is poorly understood. The m 6 A level increases in injured spinal cord, and METTL3, which is the core subunit of methyltransferase complex, is upregulated in reactive astrocytes and further stabilized by the USP1/UAF1 complex after SCI. The USP1/UAF1 complex specifically binds to and subsequently removes K48-linked ubiquitination of the METTL3 protein to maintain its stability after SCI. Moreover, conditional knockout of astrocytic METTL3 in both sexes of mice significantly suppressed reactive astrogliosis after SCI, thus resulting in widespread infiltration of inflammatory cells, aggravated neuronal loss, hampered axonal regeneration, and impaired functional recovery. Mechanistically, the YAP1 transcript was identified as a potential target of METTL3 in astrocytes. METTL3 could selectively methylate the 3′-UTR region of the YAP1 transcript, which subsequently maintains its stability in an IGF2BP2-dependent manner. In vivo , YAP1 overexpression by adeno-associated virus injection remarkably contributed to reactive astrogliosis and partly reversed the detrimental effects of METTL3 knockout on functional recovery after SCI. Furthermore, we found that the methyltransferase activity of METTL3 plays an essential role in reactive astrogliosis and motor repair, whereas METTL3 mutant without methyltransferase function failed to promote functional recovery after SCI. Our study reveals the previously unreported role of METTL3-mediated m 6 A modification in SCI and might provide a potential therapy for SCI. SIGNIFICANCE STATEMENT Spinal cord injury is a devastating trauma of the CNS involving motor and sensory impairments. However, epigenetic modification in spinal cord injury is still unclear. Here, we propose an m 6 A regulation effect of astrocytic METTL3 following spinal cord injury, and we further characterize its underlying mechanism, which might provide promising strategies for spinal cord injury treatment.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1523/JNEUROSCI.1209-22.2023
    DOI: 10.1523/JNEUROSCI.1209-22.2023.f1-1
    DOI: 10.1523/JNEUROSCI.1209-22.2023.f7-1
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2023
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  • 9
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    Online Resource
    Local Glutamate Level Dictates Adenosine A 2A Receptor Regulation of Neuroinflammation and Traumatic Brain Injury
    Society for Neuroscience ; 2010
    In:  The Journal of Neuroscience Vol. 30, No. 16 ( 2010-04-21), p. 5802-5810
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 16 ( 2010-04-21), p. 5802-5810
    Abstract: During brain injury, extracellular adenosine and glutamate levels increase rapidly and dramatically. We hypothesized that local glutamate levels in the brain dictates the adenosine–adenosine A 2A receptor (A 2A R) effects on neuroinflammation and brain damage outcome. Here, we showed that, in the presence of low concentrations of glutamate, the A 2A R agonist 3-[4-[2-[[6-amino-9-[(2 R ,3 R ,4 S ,5 S )-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl] amino]ethyl] phenyl]propanoic acid (CGS21680) inhibited lipopolysaccharide (LPS)-induced nitric oxide synthase (NOS) activity of cultured microglial cells, an effect that was dependent on the protein kinase A (PKA) pathway. However, in high concentrations of glutamate, CGS21680 increased LPS-induced NOS activity in a protein kinase C (PKC)-dependent manner. Thus, increasing the local level of glutamate redirects A 2A R signaling from the PKA to the PKC pathway, resulting in a switch in A 2A R effects from antiinflammatory to proinflammatory. In a cortical impact model of traumatic brain injury (TBI) in mice, brain water contents, behavioral deficits, and expression of tumor necrosis factor-α, interleukin-1 mRNAs, and inducible NOS were attenuated by administering CGS21680 at post-TBI time when brain glutamate levels were low, or by administering the A 2A R antagonist ZM241385 [4-(2-{[5-amino-2-(2-furyl)[1,2,4]triazolo[1,5-a] [1,3,5]triazin-7-yl] amino}ethyl)phenol] at post-TBI time when brain glutamate levels were elevated. Furthermore, pre-TBI treatment with the glutamate release inhibitor ( S )-4C3HPG [( S )-4-carboxy-3-hydroxyphenylglycine] converted the debilitating effect of CGS21680 administered at post-TBI time with high glutamate level to a neuroprotective effect. This further indicates that the switch in the effect of A 2A R activation in intact animals from antiinflammatory to proinflammatory is dependent on glutamate concentration. These findings identify a novel role for glutamate in modulation of neuroinflammation and brain injury via the adenosine–A 2A R system.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0268-10.2010
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2010
    detail.hit.zdb_id: 1475274-8
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  • 10
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    Online Resource
    The SphK1/S1P Axis Regulates Synaptic Vesicle Endocytosis via TRPC5 Channels
    Society for Neuroscience ; 2023
    In:  The Journal of Neuroscience Vol. 43, No. 21 ( 2023-05-24), p. 3807-3824
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 43, No. 21 ( 2023-05-24), p. 3807-3824
    Abstract: Sphingosine-1-phosphate (S1P), a bioactive sphingolipid concentrated in the brain, is essential for normal brain functions, such as learning and memory and feeding behaviors. Sphingosine kinase 1 (SphK1), the primary kinase responsible for S1P production in the brain, is abundant within presynaptic terminals, indicating a potential role of the SphK1/S1P axis in presynaptic physiology. Altered S1P levels have been highlighted in many neurologic diseases with endocytic malfunctions. However, it remains unknown whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis in neurons. The present study evaluates potential functions of the SphK1/S1P axis in synaptic vesicle endocytosis by determining effects of a dominant negative catalytically inactive SphK1. Our data for the first time identify a critical role of the SphK1/S1P axis in endocytosis in both neuroendocrine chromaffin cells and neurons from mice of both sexes. Furthermore, our Ca 2+ imaging data indicate that the SphK1/S1P axis may be important for presynaptic Ca 2+ increases during prolonged stimulations by regulating the Ca 2+ permeable TRPC5 channels, which per se regulate synaptic vesicle endocytosis. Collectively, our data point out a critical role of the regulation of TRPC5 by the SphK1/S1P axis in synaptic vesicle endocytosis. SIGNIFICANCE STATEMENT Sphingosine kinase 1 (SphK1), the primary kinase responsible for brain sphingosine-1-phosphate (S1P) production, is abundant within presynaptic terminals. Altered SphK1/S1P metabolisms has been highlighted in many neurologic disorders with defective synaptic vesicle endocytosis. However, whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis is unknown. Here, we identify that the SphK1/S1P axis regulates the kinetics of synaptic vesicle endocytosis in neurons, in addition to controlling fission-pore duration during single vesicle endocytosis in neuroendocrine chromaffin cells. The regulation of the SphK1/S1P axis in synaptic vesicle endocytosis is specific since it has a distinguished signaling pathway, which involves regulation of Ca 2+ influx via TRPC5 channels. This discovery may provide novel mechanistic implications for the SphK1/S1P axis in brain functions under physiological and pathologic conditions.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    URL: Article
    DOI: 10.1523/JNEUROSCI.1494-22.2023
    DOI: 10.1523/JNEUROSCI.1494-22.2023.t1-1
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2023
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