Background
Chronic but not acute treatment with antidepressants increases hippocampal neurogenesis.
Because chronic treatment with antidepressants also upregulates p11, we hypothesized
that p11 might regulate effects of antidepressants on aspects of neurogenesis.
Methods
Fluoxetine was administered chronically to wild-type (WT) and p11 knockout (KO) mice.
In the neurogenic subgranular zone of hippocampus, the effects of fluoxetine on cell
survival were examined with bromodeoxyuridine immunohistochemistry, whereas in the
same brains cell proliferation was measured with Ki-67 immunohistochemistry, neurogenesis
was measured with doublecortin immunohistochemistry, and apoptosis was measured with
activated caspase-3. The behavioral action of fluoxetine was assessed in the novelty
suppressed feeding test, which is considered neurogenesis-dependent. The localization
of p11 in the dentate gyrus was studied with immunohistochemistry.
Results
Vehicle-treated p11 KO mice have increased levels of markers for immature neuronal
cell survival and neurogenesis relative to WT mice. In response to fluoxetine, p11
KO mice have reduced cell proliferation, neurogenesis, cell survival, and cell apoptosis
in the subgranular zone of hippocampus when compared with WT littermates. P11 was
not expressed in neurogenic cells but in different subtypes of neighboring γ-aminobutyric
acid (GABA)ergic interneurons, which also express serotonin 1B and serotonin 4 receptors.
The behavioral effects of fluoxetine in the novelty suppressed feeding test were abolished
in p11 KO mice.
Conclusions
P11 is abundantly expressed in hippocampal GABAergic interneurons. The p11 KO mice
have increased levels of markers for immature neuronal cell survival and neurogenesis
and an attenuated response to fluoxetine in measures of neurogenesis and in a neurogenesis-dependent
behavioral test.
Key Words
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Article info
Publication history
Published online: March 15, 2010
Accepted:
January 24,
2010
Received in revised form:
January 20,
2010
Received:
August 27,
2009
Identification
Copyright
© 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
