Abstract
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.
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Acknowledgements
This research was supported by NIH Grant DA-011649 and CA-143187. JL Onksen was supported by a pre-doctoral NRSA (MH-087103).
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Onksen, J., Brown, E. & Blendy, J. Selective Deletion of a Cell Cycle Checkpoint Kinase (ATR) Reduces Neurogenesis and Alters Responses in Rodent Models of Behavioral Affect. Neuropsychopharmacol 36, 960–969 (2011). https://doi.org/10.1038/npp.2010.234
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DOI: https://doi.org/10.1038/npp.2010.234
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