Conditional ablation and recovery of forebrain neurogenesis in the mouse

Abstract

Forebrain neurogenesis persists throughout life in the rodent subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Several strategies have been employed to eliminate adult neurogenesis and thereby determine whether depleting adult-born neurons disrupts specific brain functions, but some approaches do not specifically target neural progenitors. We have developed a transgenic mouse line to reversibly ablate adult neural stem cells and suppress neurogenesis. The nestin-tk mouse expresses herpes simplex virus thymidine kinase (tk) under the control of the nestin 2nd intronic enhancer, which drives expression in neural progenitors. Administration of ganciclovir (GCV) kills actively dividing cells expressing this transgene. We found that peripheral GCV administration suppressed SVZ-olfactory bulb and DG neurogenesis within two weeks but caused systemic toxicity. Intracerebroventricular GCV infusion for 28 days nearly completely depleted proliferating cells and immature neurons in both the SVZ and DG without systemic toxicity. Reversibility of the effects after prolonged GCV infusion was slow and partial. Neurogenesis did not recover 2 weeks after cessation of GCV administration, but showed limited recovery 6 weeks after GCV that differed between the SVZ and DG. Suppression of neurogenesis did not inhibit antidepressant responsiveness of mice in the tail suspension test. These findings indicate that SVZ and DG neural stem cells differ in their capacity for repopulation, and that adult-born neurons are not required for antidepressant responses in a common behavioral test of antidepressant efficacy. The nestin-tk mouse should be useful for studying how reversible depletion of adult neurogenesis influences neurophysiology, other behaviors, and neural progenitor dynamics.

Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice

“…To address this question, we have examined LTP in the nestinthymidine kinase (nestin-tk) mouse model, in which herpes simplex virus (HSV) thymidine kinase expression is regulated by the nestin enhancer, enabling the specific and temporally controlled ablation of neurogenesis after the intracerebroventricular administration of ganciclovir (GCV). In this model, treatment with GCV for 28 d results in nearly complete suppression of neurogenesis in youngadult mice (26). Consistent with previous results, we found that LTP was significantly disrupted when assessed immediately following ablation.…”

“…These results suggest that the LTP deficit seen in nestin-tk mice treated with GCV is specific to the loss of newborn DGCs. Recent work suggests that 28 d of GCV treatment in nestin-tk mice results in a loss of newborn DGCs that persists for at least 42 d (6 wk) after the discontinuation of the GCV infusion (26). To determine the impact of persistently suppressed neurogenesis on LTP, experiments similar to those described above (Fig.…”

Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice

“…Expression of TK renders the cell population of interest susceptible to the cytotoxic effect of GCV (36). Studies to date have used either GFAP (20)(21)(22) or nestin (23) to direct the expression of TK. GFAP is a type III intermediate filament protein expressed classically in astrocytes, including SVZ astrocytes that give rise to neurons (37) and oligodendrocytes (38).…”

“…Several techniques have been used for this purpose, including x-irradiation (7)(8)(9)(10)(11)(12)(13), antimitotic (4,(14)(15)(16)(17)(18) or other antiproliferative (19) drugs, and conditional transgenic targeting of selected [glial fibrillary acidic protein (GFAP)-, nestin-, or homolog of Drosophila taillessexpressing] cell populations with HSV-1 thymidine kinase (TK) (20)(21)(22)(23) or inducible recombination (24). However, studies that use these ablation techniques to assess the functional significance of neurogenesis can be difficult to interpret, because ablation may be accompanied by inflammatory responses with microglial activation (7), alterations in microvascular anatomy (7), systemic toxicity (18), or involvement of nonneuronal cell lineages (25).…”

Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine

“…Indeed, it was shown that animals with blocked adult neurogenesis do not recover from depressionlike behavior when chronically administered with ADs (Santarelli et al, 2003;Surget et al, 2008;David et al, 2009;Onksen et al, 2011;Perera et al, 2011). However, recent studies suggest both neurogenesis-dependent and independent mechanisms underlying ADs action, as more studies show none or only partial effect of reducing neurogenesis on restoration of behavioral homeostasis by ADs (Meshi et al, 2006;David et al, 2007;Holick et al, 2008;Surget et al, 2008;Bessa et al, 2009a;David et al, 2009;Singer et al, 2009;Nollet et al, 2012).…”