BACKGROUND: There is a critical time window of post-stroke neuroplasticity when spontaneous behavioral recovery occurs. Potential factors responsible for this heightened plasticity are the reduction of parvalbumin-immunoreactive (PV+) interneuron inhibitory signaling and the disappearance of extracellular matrix synaptic stabilizers called perineuronal net(s; PNN/PNNs). OBJECTIVE: This study investigated whether behavioral recovery during this critical period following stroke is associated with changes in densities of PV+ interneurons and PNNs.MethodsMale, Sprague-Dawley rats received forelimb motor cortex stroke (n = 43) using endothelin-1, or vehicle injections (n = 44). Cohorts of rats underwent a battery of motor tests and were sacrificed within the post-stroke critical window on day 1, and 1, 2, 4, and 6 weeks. Using immunofluorescent labeling, PNNs (wisteria floribunda agglutinin; WFA+ cells), PV+ interneurons, and cells expressing both PV and PNNs were quantified in contra- and ipsilesional cortices to elucidate their spatial-temporal profiles following stroke.ResultsPV+ interneuron density decreased significantly at 1-day post-stroke in the lateral ipsilesional cortex, while the density of PNNs was significantly lower up to 4 weeks post-stroke in the lateral ipsilesional cortex and at 1 and 2 weeks post-stroke in the medial ipsilesional cortex. Reduction of combined PV+/PNN signaling coincided with spontaneous behavioral recovery.ConclusionsThese results suggest that post-stroke behavioral recovery corresponds to an early reduction in PV+/PNN co-labeled cells in conjunction with an early temporally-dependent reduction in PV+ interneuron signaling and chronic disappearance of PNNs. Interventions targeting PNNs or PV+ interneuron signaling have significant potential for extending the critical window of recovery following stroke.