Conditional Ablation of Neuroprogenitor Cells in Adult Mice Impedes Recovery of Poststroke Cognitive Function and Reduces Synaptic Connectivity in the Perforant Pathway

Abstract

The causal relationship between neurogenesis and the recovery of poststroke cognitive function has not been properly explored. The current study aimed to determine whether depleting neuroprogenitor cells (NPCs) affects poststroke functional outcome in nestin-␦-HSV-TK-EGFP transgenic mice, in which the expression of a truncated viral thymidine kinase gene and EGFP was restricted to nestinexpressing NPCs. Ganciclovir (GCV; 200 mg/kg/d) or saline was continuously administered via osmotic pumps in mice for 4 weeks before the induction of experimental stroke. Both baseline and stroke-induced type 1 and type 2 NPCs were conditionally ablated. GCV eliminated NPCs in a duration-dependent fashion, but it did not attenuate the genesis of astroglia or oligodendrocytes in the peri-infarct cortex, nor did it affect infarct size or cerebral blood reperfusion after stroke. Transgenic stroke mice given GCV displayed impaired spatial learning and memory in the Barnes maze test compared with saline control or wild-type stroke mice given GCV, suggesting a contributing role of stroke-induced neurogenesis in the recovery of cognitive function. However, there was no significant difference in poststroke motor function between transgenic mice treated with GCV and those treated with vehicle, despite a significant ablation of NPCs in the subventricular zone of the former. Furthermore, nestin-␦-HSV-TK-EGFP mice treated with GCV had fewer retrogradely labeled neurons in the entorhinal cortex (EC) when injected with the polysynaptic viral marker PRV614 in the dentate gyrus (DG), suggesting that there might be reduced synaptic connectivity between the DG and EC following ablation of NPCs, which may contribute to impaired poststroke memory function.

Predicting Outcome after Pediatric Traumatic Brain Injury by Early Magnetic Resonance Imaging Lesion Location and Volume

“…63 Recent animal experiments have shown that ablation of these immature precursors can interfere with recovery from brain injury and impair restoration of spatial learning and memory as well as cognitive and motor function. [64][65][66][67] Because myelination, synaptogenesis, and neural organization occur throughout childhood, it is plausible that neural self-repair and adaptive potential is, in part, determined by the consequence of traumatic interruption of immature neural networks. Hence, injury to deep brain structures, which are immature and evolving in younger children, resulted in a greater influence on functional recovery, whereas in adolescents organizing and developing cortical regions exert a more dominant impact.…”

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

“…Impaired neurogenesis (Acosta et al, 2013; Esposito, Hayakawa, Maki, Arai, & Lo, 2015; Kokaia & Darsalia, 2011; Sun et al, 2013, 2016; Xia et al, 2006; Zhang et al, 2012) accompanies many neurological disorders, including stroke. Enhancement of host neurogenesis may serve as a novel therapy for stroke, which remains a significant unmet clinical need with efficacy of tissue plasminogen activator or tPA limited to 4.5 hr.…”

“…In this study, we tested in a stroke model the therapeutic effects of NSI‐189, a small molecule with enhanced neurogenic activity, which is already in clinical trial for treatment of major depression and prevention against suicide (ClinicalTrials.gov, 2016; Fava et al, 2015). While the brain exerts self‐repair acutely, over time the stroke‐induced cascade of cell death events outweighs the endogenous regenerative mechanisms (Acosta et al, 2013; Fava et al, 2015; Kokaia & Darsalia, 2011; Sun et al, 2013, 2016; Zhang et al, 2012). Thus, finding a therapeutic strategy to stimulate the brain to mount a prolonged and stable reparative machinery during the secondary cell death progression after stroke will likely afford beneficial effects.…”

Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia

“…However, differing from normal circumstances, pathological conditions such as cerebral ischemia could stimulate neurogenesis in SVZ and directed migration of newly formed neural progenitor cells toward the infarct area (Jin et al, 2001;Zhang et al, 2001;Yamashita et al, 2006). Furthermore, such injuryinduced neurogenesis is supposed to contribute to stroke outcome (Raber et al, 2004;Jin et al, 2010;Sun et al, 2012Sun et al, , 2013Sun et al, , 2015Wang et al, 2012). There is therefore an urgent need for a better understanding of injuryinduced neurogenesis in adult mammals.…”