Conditional ablation and recovery of forebrain neurogenesis in the mouse.
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 2 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.
Singer
Benjamin H
BH
Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Jutkiewicz
Emily M
EM
Fuller
Cynthia L
CL
Lichtenwalner
Robin J
RJ
Zhang
Helen
H
Velander
Alan J
AJ
Li
Xiangquan
X
Gnegy
Margaret E
ME
Burant
Charles F
CF
Parent
Jack M
JM
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology; D015774:Ganciclovir / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000235:genetics; D019417:Hindlimb Suspension; D007099:Imipramine / Q000627:therapeutic use; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D013937:Thymidine Kinase / Q000235:genetics
D000929:Antidepressive Agents, Tricyclic; D000998:Antiviral Agents; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D013937:Thymidine Kinase; D007099:Imipramine; D015774:Ganciclovir