Selective deletion of a cell cycle checkpoint kinase (ATR) reduces neurogenesis and alters responses in rodent models of behavioral affect.
Hippocampal function has been implicated in mood and anxiety disorders, as well as in the response to antidepressant (AD) treatment. However, the significance of new neurons in the therapeutic mechanism of ADs remains unclear. In this study, the proliferation of new neurons was inhibited through conditional deletion of ataxia telangeictasia-mutated and rad-3 related (ATR), a cell cycle checkpoint kinase, and cellular and behavioral outcomes following AD exposure were evaluated. ATR was conditionally deleted by microinjecting a Cre recombinase-expressing virus into the hippocampus of floxed-ATR mice. Behavioral assessment in multiple rodent models of affective state revealed anxiolytic-like behavior in the elevated zero maze, marble burying test, and novelty-induced hypophagia (NIH) test. The efficacy of chronic desipramine (DMI) treatment was evaluated in the NIH test, as this paradigm is thought to be sensitive to increases in neurogenesis by chronic AD exposure. Chronic exposure to DMI reduced hyponeophagia in the NIH test in control mice, whereas DMI had no behavioral effect in ATR-deleted mice. Although DMI did not alter cell proliferation in either group, it did produce a robust increase in dendritic spine density in control mice, indicative of enhanced neuronal plasticity. This effect of DMI on spine density was severely attenuated following ATR deletion. These findings demonstrate that reductions in basal neurogenesis produce an anxiolytic phenotype and reduce AD efficacy in behaviors requiring chronic exposure. Furthermore, attenuated capacity for synaptic remodeling may underlie these behaviors. ATR deletion may serve as a valuable model to study the various proposed roles of newborn neurons in the hippocampus.
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Jennifer L
JL
Onksen
Eric J
EJ
Brown
Julie A
JA
Blendy
D000342:Affective Symptoms / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D001522:Behavior, Animal / Q000502:physiology; D001973:Bromodeoxyuridine / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002707:Chlordiazepoxide / Q000494:pharmacology; D049229:Dendritic Spines / Q000187:drug effects / Q000648:ultrastructure; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007093:Imidazoles / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D016622:Silver Staining / Q000379:methods; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013550:Swimming / Q000523:psychology; D014161:Transduction, Genetic / Q000379:methods
D014151:Anti-Anxiety Agents; D018797:Cell Cycle Proteins; D007093:Imidazoles; C499429:N-dodecyl-2-mercaptoimidazole; D013438:Sulfhydryl Compounds; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D002707:Chlordiazepoxide; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D001973:Bromodeoxyuridine
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