Archival Report| Volume 67, ISSUE 11, P1048-1056, June 01, 2010

Neurogenic Effects of Fluoxetine Are Attenuated in p11 (S100A10) Knockout Mice


      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.


      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.


      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.


      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

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Malberg J.E.
        • Eisch A.J.
        • Nestler E.J.
        • Duman R.S.
        Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.
        J Neurosci. 2000; 20: 9104-9110
        • Santarelli L.
        • Saxe M.
        • Gross C.
        • Surget A.
        • Battaglia F.
        • Dulawa S.
        • et al.
        Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.
        Science. 2003; 301: 805-809
        • Sairanen M.
        • Lucas G.
        • Ernfors P.
        • Castren M.
        • Castren E.
        Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus.
        J Neurosci. 2005; 25: 1089-1094
        • Sahay A.
        • Hen R.
        Adult hippocampal neurogenesis in depression.
        Nat Neurosci. 2007; 10: 1110-1115
        • David D.J.
        • Samuels B.A.
        • Rainer Q.
        • Wang J.W.
        • Marsteller D.
        • Mendez I.
        • et al.
        Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression.
        Neuron. 2009; 62: 479-493
        • Svenningsson P.
        • Chergui K.
        • Rachleff I.
        • Flajolet M.
        • Zhang X.
        • El Yacoubi M.
        • et al.
        Alterations in 5-HT1B receptor function by p11 in depression-like states.
        Science. 2006; 311: 77-80
        • Warner-Schmidt J.L.
        • Flajolet M.
        • Maller A.
        • Chen E.Y.
        • Qi H.
        • Svenningsson P.
        • et al.
        Role of p11 in cellular and behavioral effects of 5-HT4 receptor stimulation.
        J Neurosci. 2009; 29: 1937-1946
        • Anisman H.
        • Du L.
        • Palkovits M.
        • Faludi G.
        • Kovacs G.G.
        • Szontagh-Kishazi P.
        • et al.
        Serotonin receptor subtype and p11 mRNA expression in stress-relevant brain regions of suicide and control subjects.
        J Psychiatry Neurosci. 2008; 33: 131-141
        • Kee N.
        • Sivalingam S.
        • Boonstra R.
        • Wojtowicz J.M.
        The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis.
        J Neurosci Methods. 2002; 115: 97-105
        • Carlen M.
        • Cassidy R.M.
        • Brismar H.
        • Smith G.A.
        • Enquist L.W.
        • Frisen J.
        Functional integration of adult-born neurons.
        Curr Biol. 2002; 12: 606-608
        • Couillard-Despres S.
        • Winner B.
        • Schaubeck S.
        • Aigner R.
        • Vroemen M.
        • Weidner N.
        • et al.
        Doublecortin expression levels in adult brain reflect neurogenesis.
        Eur J Neurosci. 2005; 21: 1-14
        • Bruinvels A.T.
        • Landwehrmeyer B.
        • Gustafson E.L.
        • Durkin M.M.
        • Mengod G.
        • Branchek T.A.
        • et al.
        Localization of 5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain.
        Neuropharmacology. 1994; 33: 367-386
        • Waeber C.
        • Sebben M.
        • Nieoullon A.
        • Bockaert J.
        • Dumuis A.
        Regional distribution and ontogeny of 5-HT4 binding sites in rodent brain.
        Neuropharmacology. 1994; 33: 527-541
        • Tozuka Y.
        • Fukuda S.
        • Namba T.
        • Seki T.
        • Hisatsune T.
        GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells.
        Neuron. 2005; 47: 803-815
        • Ge S.
        • Goh E.L.
        • Sailor K.A.
        • Kitabatake Y.
        • Ming G.L.
        • Song H.
        GABA regulates synaptic integration of newly generated neurons in the adult brain.
        Nature. 2006; 439: 589-593
        • Wu X.
        • Castren E.
        Co-treatment with diazepam prevents the effects of fluoxetine on the proliferation and survival of hippocampal dentate granule cells.
        Biol Psychiatry. 2009; 66: 5-8
        • Halasy K.
        • Miettinen R.
        • Szabat E.
        • Freund T.F.
        GABAergic interneurons are the major postsynaptic targets of median Raphe afferents in the Rat dentate gyrus.
        Eur J Neurosci. 1992; 4: 144-153
        • Freund T.F.
        • Gulyas A.I.
        • Acsady L.
        • Gorcs T.
        • Toth K.
        Serotonergic control of the hippocampus via local inhibitory interneurons.
        Proc Natl Acad Sci U S A. 1990; 87: 8501-8505
        • Freund T.F.
        • Buzsaki G.
        Interneurons of the hippocampus.
        Hippocampus. 1996; 6: 347-470
        • Banasr M.
        • Hery M.
        • Printemps R.
        • Daszuta A.
        Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone.
        Neuropsychopharmacology. 2004; 29: 450-460
        • Lucas G.
        • Rymar V.V.
        • Du J.
        • Mnie-Filali O.
        • Bisgaard C.
        • Manta S.
        • et al.
        Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action.
        Neuron. 2007; 55: 712-725
        • Svenningsson P.
        • Greengard P.
        p11 (S100A10)—an inducible adaptor protein that modulates neuronal functions.
        Curr Opin Pharmacol. 2007; 7: 27-32
        • Heurteaux C.
        • Lucas G.
        • Guy N.
        • El Yacoubi M.
        • Thummler S.
        • Peng X.D.
        • et al.
        Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype.
        Nat Neurosci. 2006; 9: 1134-1141
        • Kwon M.
        • MacLeod T.J.
        • Zhang Y.
        • Waisman D.M.
        S100A10, annexin A2, and annexin A2 heterotetramer as candidate plasminogen receptors.
        Front Biosci. 2005; 10: 300-325
        • Pawlak R.
        • Rao B.S.
        • Melchor J.P.
        • Chattarji S.
        • McEwen B.
        • Strickland S.
        Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus.
        Proc Natl Acad Sci U S A. 2005; 102: 18201-18206
        • Pang P.T.
        • Teng H.K.
        • Zaitsev E.
        • Woo N.T.
        • Sakata K.
        • Zhen S.
        • et al.
        Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity.
        Science. 2004; 306: 487-491
        • Wang J.W.
        • David D.J.
        • Monckton J.E.
        • Battaglia F.
        • Hen R.
        Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells.
        J Neurosci. 2008; 28: 1374-1384