PSD-95 uncoupling from NMDA receptors by Tat- N-dimer ameliorates neuronal depolarization in cortical spreading depression.
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 depolarization wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling in stroke.
1 Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen N, Denmark.
Krzysztof
K
Kucharz
1 Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen N, Denmark.
Ida
I
Søndergaard Rasmussen
2 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen Ø, Denmark.
Anders
A
Bach
2 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen Ø, Denmark.
Kristian
K
Strømgaard
1 Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen N, Denmark.|3 Department of Clinical Neurophysiology, Glostrup Hospital, Glostrup, Denmark.
Martin
M
Lauritzen
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D013181:Cortical Spreading Depression / Q000187:drug effects* / Q000502:physiology; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D055366:Synaptic Potentials / Q000187:drug effects
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C571729:Tat-NPEG4(IETDV)2; D051528:Guanylate Kinases
Cortical spreading depression; NMDAR; Tat-N-dimer; UCCB01-144; postsynaptic density protein 95; spreading depolarization; stroke