Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice.
Injury stimulates neurogenesis in the adult brain, but the role of injury-induced neurogenesis in brain repair and recovery is uncertain. One strategy for investigating this issue is to ablate neuronal precursors and thereby prevent neurogenesis, but this is difficult to achieve in a specific fashion. We produced transgenic mice that express herpes simplex virus thymidine kinase (TK) under control of the promoter for doublecortin (Dcx), a microtubule-associated protein expressed in newborn and migrating neurons. Treatment for 14 days with the antiviral drug ganciclovir (GCV) depleted Dcx-expressing and BrdU-labeled cells from the rostral subventricular zone and dentate gyrus, and abolished neurogenesis and associated neuromigration induced by focal cerebral ischemia. GCV treatment of Dcx-TK transgenic, but not WT, mice also increased infarct size and exacerbated postischemic sensorimotor behavioral deficits measured by rotarod, limb placing, and elevated body swing tests. These findings provide evidence that injury-induced neurogenesis contributes to stroke outcome and might therefore be a target for stroke therapy.
Jin
Kunlin
K
Buck Institute for Age Research, Novato, CA 94945, USA.
Wang
Xiaomei
X
Xie
Lin
L
Mao
Xiao Ou
XO
Greenberg
David A
DA
D055011:Ablation Techniques; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D001973:Bromodeoxyuridine; D017931:DNA Primers / Q000235:genetics; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D015774:Ganciclovir / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D045442:Rotarod Performance Test; D018139:Simplexvirus / Q000201:enzymology; D020521:Stroke / Q000503:physiopathology*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine; D015774:Ganciclovir
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