title: 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-δ-HSV-TK-EGFP transgenic mice, in which the expression of a truncated viral thymidine kinase gene and EGFP was restricted to nestin-expressing 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-δ-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.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94121, San Francisco VA Medical Center, San Francisco, California 94121, Department of Neurological Surgery, Second Affiliated Hospital of Zhejiang University Medical College, Hangzhou 310009, China, Department of Neurological Surgery, Xinhua Hospital, Shanghai Jiaotong University, Shanghai 201101, China, Department of Neurological Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8574, Japan, Departments of Bioengineering and Ophthalmology, University of Washington, Seattle, Washington 98195, and Departments of Pediatrics, Pathology and Cell Biology, Columbia University, New York, New York 10032.
authors.forename: Chongran
authors.initials: C
authors.lastname: Sun
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Steven
authors.initials: S
authors.lastname: Wu
authors.forename: Chih Cheng
authors.initials: CC
authors.lastname: Lee
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Akamatsu
authors.forename: Ruikang K
authors.initials: RK
authors.lastname: Wang
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kernie
authors.forename: Jialing
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000473:pathology / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D019580:Perforant Pathway / Q000473:pathology* / Q000502:physiology; D020127:Recovery of Function / Q000502:physiology*; D020521:Stroke / Q000473:pathology* / Q000523:psychology; D013569:Synapses / Q000473:pathology / Q000502:physiology*