Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice
María Isabel Cuartero, … , Ignacio Lizasoain, María Ángeles Moro
María Isabel Cuartero, … , Ignacio Lizasoain, María Ángeles Moro
Published January 24, 2019
Citation Information: J Clin Invest. 2019;129(4):1536-1550. https://doi.org/10.1172/JCI120412.
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Research Article Neuroscience

Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice

Abstract

Poststroke cognitive impairment is considered one of the main complications during the chronic phase of ischemic stroke. In the adult brain, the hippocampus regulates both encoding and retrieval of new information through adult neurogenesis. Nevertheless, the lack of predictive models and studies based on the forgetting processes hinders the understanding of memory alterations after stroke. Our aim was to explore whether poststroke neurogenesis participates in the development of long-term memory impairment. Here, we show a hippocampal neurogenesis burst that persisted 1 month after stroke and that correlated with an impaired contextual and spatial memory performance. Furthermore, we demonstrate that the enhancement of hippocampal neurogenesis after stroke by physical activity or memantine treatment weakened existing memories. More importantly, stroke-induced newborn neurons promoted an aberrant hippocampal circuitry remodeling with differential features at ipsi- and contralesional levels. Strikingly, inhibition of stroke-induced hippocampal neurogenesis by temozolomide treatment or using a genetic approach (Nestin-CreERT2/NSE-DTA mice) impeded the forgetting of old memories. These results suggest that hippocampal neurogenesis modulation could be considered as a potential approach for treatment of poststroke cognitive impairment.

Authors

María Isabel Cuartero, Juan de la Parra, Alberto Pérez-Ruiz, Isabel Bravo-Ferrer, Violeta Durán-Laforet, Alicia García-Culebras, Juan Manuel García-Segura, Jagroop Dhaliwal, Paul W. Frankland, Ignacio Lizasoain, María Ángeles Moro

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Figure 5

Altered features of newborn neurons induced by stroke.

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Altered features of newborn neurons induced by stroke. (A) Experimental ...
(A) Experimental design for GFP retroviral labeling of newborn neurons. (B) Representative images of GFP newborn neurons of each group. Yellow arrow, 112 μm. (C) Sholl analysis of GFP newborn neurons in sham-operated and MCAO groups, 28 days after infection. Two-way ANOVA demonstrates a significant interaction between distance and experimental group in the number of intersections (F(48,3022) = 5.18; P < 0.0001; Bonferroni’s post hoc: *P < 0.05 vs. sham operated; #P < 0.05 vs. MCAO ipsilesional; sham operated, n = 52 neurons/4 mice; MCAO ipsilesional, n = 41 neurons/4 mice; MCAO contralesional, n = 32 neurons/3 mice). (D) Mean average intersections of GFP neurons at different intervals from soma. (*P < 0.05 vs. sham operated; #P < 0.05 vs. MCAO ipsilesional; sham operated, n = 52 neurons/4 mice; MCAO ipsilesional, n = 41 neurons/4 mice; MCAO contralesional, n = 32 neurons/3 mice). (E and F) Quantification of total dendritic length (E, *P < 0.05 vs. sham operated; #P < 0.05 vs. MCAO ipsilesional, respectively; sham operated, n = 18 neurons/4 mice; MCAO ipsilesional, n = 45 neurons/4 mice; MCAO contralesional, n = 29 neurons/3 mice), and apical dendritic length (F, *P < 0.05 vs. sham operated; #P < 0.05 MCAO vs. ipsilesional; sham operated, n = 61 neurons/4 mice; MCAO ipsilesional, n = 60 neurons/4 mice; MCAO contralesional, n = 40 neurons/3 mice) in sham-operated and both ipsi- and contralesional sides of MCAO group. (G) Pie charts display percentage of GFP+ neurons in each group showing apical dendrite lengths of less than 10 μm, 10–40 μm, and more than 40 μm (sham operated, n = 61 neurons/4 mice; MCAO ipsilesional n = 60 neurons/4 mice; MCAO contralesional, n = 40 neurons/3 mice). Data are represented as mean ± SEM. Data were compared by using nonparametric 2-tailed Mann-Whitney U tests (D–F) and nonparametric 2-way ANOVA followed by Bonferroni’s post hoc testing (C).