Uncoupling PSD-95 interactions leads to rapid recovery of cortical function after focal stroke.

Since the most significant ischemic sequelae occur within hours of stroke, it is necessary to understand how neuronal function changes during this time. While histologic and behavioral models show the extent of stroke-related damage, only in vivo recordings can illustrate changes in brain activity during stroke and validate effectiveness of neuroprotective compounds. Spontaneous and evoked field potentials (fEPs) were recorded in the deep layers of the cortex with a linear microelectrode array for 3 hours after focal stroke in anesthetized rats. Tat-NR2B9c peptide, which confers neuroprotection by uncoupling the PSD-95 protein from N-methyl-D-aspartate receptor (NMDAR), was administered 5 minutes before ischemia. Evoked field potentials were completely suppressed within 3 minutes of infarct in all ischemic groups. Evoked field potential recovery after stroke in rats treated with Tat-NR2B9c (83% of baseline) was greater compared with stroke-only (61% of baseline) or control peptide (Tat-NR2B-AA; 67% of baseline) groups (P<0.001). Electroencephalography (EEG) power was higher in Tat-NR2B9c-treated animals at both 20 minutes and 1 hour (50% and 73% of baseline, respectively) compared with stroke-only and Tat-NR2B-AA-treated rats (P<0.05). Tat-NR2B9c significantly reduces stroke-related cortical dysfunction as evidenced by greater recovery of fEPs and EEG power; illustrating the immediate effects of the compound on poststroke brain function.