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  • 1
    Online Resource
    Online Resource
    Deficiency of AMPAR–Palmitoylation Aggravates Seizure Susceptibility
    Society for Neuroscience ; 2018
    In:  The Journal of Neuroscience Vol. 38, No. 47 ( 2018-11-21), p. 10220-10235
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 38, No. 47 ( 2018-11-21), p. 10220-10235
    Abstract: Synaptic AMPAR expression controls the strength of excitatory synaptic transmission and plasticity. An excess of synaptic AMPARs leads to epilepsy in response to seizure-inducible stimulation. The appropriate regulation of AMPARs plays a crucial role in the maintenance of the excitatory/inhibitory synaptic balance; however, the detailed mechanisms underlying epilepsy remain unclear. Our previous studies have revealed that a key modification of AMPAR trafficking to and from postsynaptic membranes is the reversible, posttranslational S -palmitoylation at the C-termini of receptors. To clarify the role of palmitoylation-dependent regulation of AMPARs in vivo , we generated GluA1 palmitoylation-deficient (Cys811 to Ser substitution) knock-in mice. These mutant male mice showed elevated seizure susceptibility and seizure-induced neuronal activity without impairments in synaptic transmission, gross brain structure, or behavior at the basal level. Disruption of the palmitoylation site was accompanied by upregulated GluA1 phosphorylation at Ser831, but not at Ser845, in the hippocampus and increased GluA1 protein expression in the cortex. Furthermore, GluA1 palmitoylation suppressed excessive spine enlargement above a certain size after LTP. Our findings indicate that an abnormality in GluA1 palmitoylation can lead to hyperexcitability in the cerebrum, which negatively affects the maintenance of network stability, resulting in epileptic seizures. SIGNIFICANCE STATEMENT AMPARs predominantly mediate excitatory synaptic transmission. AMPARs are regulated in a posttranslational, palmitoylation-dependent manner in excitatory synapses of the mammalian brain. Reversible palmitoylation dynamically controls synaptic expression and intracellular trafficking of the receptors. Here, we generated GluA1 palmitoylation-deficient knock-in mice to clarify the role of AMPAR palmitoylation in vivo . We showed that an abnormality in GluA1 palmitoylation led to hyperexcitability, resulting in epileptic seizure. This is the first identification of a specific palmitoylated protein critical for the seizure-suppressing process. Our data also provide insight into how predicted receptors such as AMPARs can effectively preserve network stability in the brain. Furthermore, these findings help to define novel key targets for developing anti-epileptic drugs.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1523/JNEUROSCI.1590-18.2018
    DOI: 10.1523/JNEUROSCI.1590-18.2018.f1-1
    DOI: 10.1523/JNEUROSCI.1590-18.2018.f3-1
    DOI: 10.1523/JNEUROSCI.1590-18.2018.f5-1
    DOI: 10.1523/JNEUROSCI.1590-18.2018.f6-1
    DOI: 10.1523/JNEUROSCI.1590-18.2018.f7-1
    DOI: 10.1523/JNEUROSCI.1590-18.2018.f9-1
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2018
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    The excess attenuation of outdoor noise propagating over the ground
    Acoustical Society of America (ASA) ; 1978
    In:  The Journal of the Acoustical Society of America Vol. 64, No. S1 ( 1978-11-01), p. S172-S172
    Details
    In: The Journal of the Acoustical Society of America, Acoustical Society of America (ASA), Vol. 64, No. S1 ( 1978-11-01), p. S172-S172
    Abstract: The field experiments of the noise propagating over the ground were carried out, varying the combination of height of an artificial noise source and a receiving point. We pay attention to the excess attenuation obtained from the noise propagating over the ground. The results obtained are as follows: (1) The excess attenuation of the low frequency obtained from the noise propagating over the soft ground is larger than we expected and also affected by the wind; (2) the excess attenuation obtained is, as a whole, larger in summer than in winter. From the data obtained, the empirical equation predicting the excess attenuation is introduced. [T. F. Embleton, J. E. Piercy, and N. Olson, J. Acoust. Soc. Am. 59, 267–277 (1976)] Furthermore, referring to the data measured by other researchers [P. H. Parkin and W. E. Scholes, J. Sound Vib. 2, 353–374 (1965)] , it is shown that the equation is applicable to predict the excess attenuation over the ground.
    Type of Medium: Online Resource
    ISSN: 0001-4966 , 1520-8524
    URL: Article
    DOI: 10.1121/1.2004016
    RVK:
    EQ 1000
    Language: English
    Publisher: Acoustical Society of America (ASA)
    Publication Date: 1978
    detail.hit.zdb_id: 1461063-2
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  • 3
    Online Resource
    Online Resource
    A Novel Allosteric Potentiator of AMPA Receptors: 4-[2-(Phenylsulfonylamino)ethylthio]-2,6-Difluoro-Phenoxyacetamide
    Society for Neuroscience ; 1997
    In:  The Journal of Neuroscience Vol. 17, No. 15 ( 1997-08-01), p. 5760-5771
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 17, No. 15 ( 1997-08-01), p. 5760-5771
    Abstract: We report that a novel sulfonylamino compound, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA), selectively potentiates glutamate receptors of the AMPA subtype. PEPA (1–200 μ m ) dose dependently potentiated glutamate-evoked currents in Xenopus oocytes expressing AMPA (GluRA–GluRD), but not kainate (GluR6 and GluR6+KA2) or NMDA (ζ1 + ε1–ε4), receptor subunits. PEPA was effective at micromolar concentrations and, in contrast to the action of cyclothiazide, preferentially modulated AMPA receptor flop isoforms. At 200 μ m , PEPA potentiated glutamate responses by 50-fold in oocytes expressing GluRC flop (EC 50 ∼50 μ m ) versus only threefold for GluRC flip ; a similar preference for flop isoforms was observed for other AMPA receptor subunits. Dose–response analysis for GluRC flop revealed that 100 μ m PEPA produced a sevenfold increase in AMPA receptor affinity for glutamate. PEPA produced considerably weaker potentiation of kainate-evoked than glutamate-evoked currents, suggesting modulation of the process of receptor desensitization. In human embryonic kidney 293 cells transfected with AMPA receptor subunits, PEPA either abolished or markedly slowed the rate of onset of desensitization and potentiated steady-state equilibrium currents evoked by glutamate with subunit (GluRC ≥ GluRD 〉 GluRA) and splice-variant (flop 〉 flip) selectivity similar to that observed in oocytes. Our results show that PEPA is a novel, flop-preferring allosteric modulator of AMPA receptor desensitization at least 100 times more potent than aniracetam.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.17-15-05760.1997
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1997
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 4
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    Online Resource
    A quantification method of somatic mutations in normal tissues and their accumulation in pediatric patients with chemotherapy
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 31 ( 2022-08-02)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 31 ( 2022-08-02)
    Abstract: Somatic mutations are accumulated in normal human tissues with aging and exposure to carcinogens. If we can accurately count any passenger mutations in any single DNA molecule, since their quantity is much larger than driver mutations, we can sensitively detect mutation accumulation in polyclonal normal tissues. Duplex sequencing, which tags both DNA strands in one DNA molecule, enables accurate count of such mutations, but requires a very large number of sequencing reads for each single sample of human-genome size. Here, we reduced the genome size to 1/90 using the Bam HI restriction enzyme and established a cost-effective pipeline. The enzymatically cleaved and optimal sequencing (EcoSeq) method was able to count somatic mutations in a single DNA molecule with a sensitivity of as low as 3 × 10 −8 per base pair (bp), as assessed by measuring artificially prepared mutations. Taking advantages of EcoSeq, we analyzed normal peripheral blood cells of pediatric sarcoma patients who received chemotherapy ( n = 10) and those who did not ( n = 10). The former had a mutation frequency of 31.2 ± 13.4 × 10 −8 per base pair while the latter had 9.0 ± 4.5 × 10 −8 per base pair ( P 〈 0.001). The increase in mutation frequency was confirmed by analysis of the same patients before and after chemotherapy, and increased mutation frequencies persisted 46 to 64 mo after chemotherapy, indicating that the mutation accumulation constitutes a risk of secondary leukemia. EcoSeq has the potential to reveal accumulation of somatic mutations and exposure to environmental factors in any DNA samples and will contribute to cancer risk estimation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2123241119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
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    Online Resource
    Regulation of Motor Representation by Phase–Amplitude Coupling in the Sensorimotor Cortex
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 44 ( 2012-10-31), p. 15467-15475
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 44 ( 2012-10-31), p. 15467-15475
    Abstract: High-γ amplitude (80–150 Hz) represents motor information, such as movement types, on the sensorimotor cortex. In several cortical areas, high-γ amplitudes are coupled with low-frequency phases, e.g., α and θ (phase–amplitude coupling, PAC). However, such coupling has not been studied in the sensorimotor cortex; thus, its potential functional role has yet to be explored. We investigated PAC of high-γ amplitude in the sensorimotor cortex during waiting for and the execution of movements using electrocorticographic (ECoG) recordings in humans. ECoG signals were recorded from the sensorimotor cortices of 4 epilepsy patients while they performed three different hand movements. A subset of electrodes showed high-γ activity selective to movement type around the timing of motor execution, while the same electrodes showed nonselective high-γ activity during the waiting period ( 〉 2 s before execution). Cross frequency coupling analysis revealed that the high-γ amplitude during waiting was strongly coupled with the α phase (10–14 Hz) at the electrodes with movement-selective high-γ amplitudes during execution. This coupling constituted the high-γ amplitude peaking around the trough of the α oscillation, and its strength and phase were not predictive of movement type. As the coupling attenuated toward the timing of motor execution, the high-γ amplitude appeared to be released from the α phase to build a motor representation with phase-independent activity. Our results suggest that PAC modulates motor representation in the sensorimotor cortex by holding and releasing high-γ activity in movement-selective cortical regions.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2929-12.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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