PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression

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PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression. / Kucharz, Krzysztof; Søndergaard Rasmussen, Ida; Bach, Anders; Strømgaard, Kristian; Lauritzen, Martin.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 37, No. 5, 2017, p. 1820-1828.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Kucharz, K, Søndergaard Rasmussen, I, Bach, A, Strømgaard, K & Lauritzen, M 2017, 'PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression', Journal of Cerebral Blood Flow and Metabolism, vol. 37, no. 5, pp. 1820-1828. https://doi.org/10.1177/0271678X16645595

APA

Kucharz, K., Søndergaard Rasmussen, I., Bach, A., Strømgaard, K., & Lauritzen, M. (2017). PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression. Journal of Cerebral Blood Flow and Metabolism, 37(5), 1820-1828. https://doi.org/10.1177/0271678X16645595

Vancouver

Kucharz K, Søndergaard Rasmussen I, Bach A, Strømgaard K, Lauritzen M. PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression. Journal of Cerebral Blood Flow and Metabolism. 2017;37(5):1820-1828. https://doi.org/10.1177/0271678X16645595

Author

Kucharz, Krzysztof ; Søndergaard Rasmussen, Ida ; Bach, Anders ; Strømgaard, Kristian ; Lauritzen, Martin. / PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression. In: Journal of Cerebral Blood Flow and Metabolism. 2017 ; Vol. 37, No. 5. pp. 1820-1828.

Bibtex

@article{b2159a8c33ab4a35ade2beee46bcb672,
title = "PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression",
abstract = "Cortical spreading depression is associated with activation of NMDA receptors, which interact with the postsynaptic density protein 95 (PSD-95) that binds to nitric oxide synthase (nNOS). Here, we tested whether inhibition of the nNOS/PSD-95/NMDA receptor complex formation by anti-ischemic compound, UCCB01-144 (Tat-N-dimer) ameliorates the persistent effects of cortical spreading depression on cortical function. Using in vivo two-photon microscopy in somatosensory cortex in mice, we show that fluorescently labelled Tat-N-dimer readily crosses blood-brain barrier and accumulates in nerve cells during the first hour after i.v. injection. The Tat-N-dimer suppressed stimulation-evoked synaptic activity by 2-20{\%}, while cortical blood flow and cerebral oxygen metabolic (CMRO2) responses were preserved. During cortical spreading depression, the Tat-N-dimer reduced the average amplitude of the negative shift in direct current potential by 33{\%} (4.1 mV). Furthermore, the compound diminished the average depression of spontaneous electrocorticographic activity by 11{\%} during first 40 min of post-cortical spreading depression recovery, but did not mitigate the suppressing effect of cortical spreading depression on cortical blood flow and CMRO2 We suggest that uncoupling of PSD-95 from NMDA receptors reduces overall neuronal excitability and the amplitude of the spreading depolarisation wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling in stroke.",
author = "Krzysztof Kucharz and {S{\o}ndergaard Rasmussen}, Ida and Anders Bach and Kristian Str{\o}mgaard and Martin Lauritzen",
note = "{\circledC} The Author(s) 2016.",
year = "2017",
doi = "10.1177/0271678X16645595",
language = "English",
volume = "37",
pages = "1820--1828",
journal = "Journal of Cerebral Blood Flow and Metabolism",
issn = "0271-678X",
publisher = "SAGE Publications",
number = "5",

}

RIS

TY - JOUR

T1 - PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression

AU - Kucharz, Krzysztof

AU - Søndergaard Rasmussen, Ida

AU - Bach, Anders

AU - Strømgaard, Kristian

AU - Lauritzen, Martin

N1 - © The Author(s) 2016.

PY - 2017

Y1 - 2017

N2 - Cortical spreading depression is associated with activation of NMDA receptors, which interact with the postsynaptic density protein 95 (PSD-95) that binds to nitric oxide synthase (nNOS). Here, we tested whether inhibition of the nNOS/PSD-95/NMDA receptor complex formation by anti-ischemic compound, UCCB01-144 (Tat-N-dimer) ameliorates the persistent effects of cortical spreading depression on cortical function. Using in vivo two-photon microscopy in somatosensory cortex in mice, we show that fluorescently labelled Tat-N-dimer readily crosses blood-brain barrier and accumulates in nerve cells during the first hour after i.v. injection. The Tat-N-dimer suppressed stimulation-evoked synaptic activity by 2-20%, while cortical blood flow and cerebral oxygen metabolic (CMRO2) responses were preserved. During cortical spreading depression, the Tat-N-dimer reduced the average amplitude of the negative shift in direct current potential by 33% (4.1 mV). Furthermore, the compound diminished the average depression of spontaneous electrocorticographic activity by 11% during first 40 min of post-cortical spreading depression recovery, but did not mitigate the suppressing effect of cortical spreading depression on cortical blood flow and CMRO2 We suggest that uncoupling of PSD-95 from NMDA receptors reduces overall neuronal excitability and the amplitude of the spreading depolarisation wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling in stroke.

AB - Cortical spreading depression is associated with activation of NMDA receptors, which interact with the postsynaptic density protein 95 (PSD-95) that binds to nitric oxide synthase (nNOS). Here, we tested whether inhibition of the nNOS/PSD-95/NMDA receptor complex formation by anti-ischemic compound, UCCB01-144 (Tat-N-dimer) ameliorates the persistent effects of cortical spreading depression on cortical function. Using in vivo two-photon microscopy in somatosensory cortex in mice, we show that fluorescently labelled Tat-N-dimer readily crosses blood-brain barrier and accumulates in nerve cells during the first hour after i.v. injection. The Tat-N-dimer suppressed stimulation-evoked synaptic activity by 2-20%, while cortical blood flow and cerebral oxygen metabolic (CMRO2) responses were preserved. During cortical spreading depression, the Tat-N-dimer reduced the average amplitude of the negative shift in direct current potential by 33% (4.1 mV). Furthermore, the compound diminished the average depression of spontaneous electrocorticographic activity by 11% during first 40 min of post-cortical spreading depression recovery, but did not mitigate the suppressing effect of cortical spreading depression on cortical blood flow and CMRO2 We suggest that uncoupling of PSD-95 from NMDA receptors reduces overall neuronal excitability and the amplitude of the spreading depolarisation wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling in stroke.

U2 - 10.1177/0271678X16645595

DO - 10.1177/0271678X16645595

M3 - Journal article

VL - 37

SP - 1820

EP - 1828

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 5

ER -

ID: 162458306