Figure 4.

Brain-derived neurotrophic factor (BDNF), Wnt2 and 15-Deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) act synergistically on the hippocampus by decreasing miR-16 and increasing serotonin transporter (SERT) and bcl-2 levels. (a–c) Mice received a chronic perfusion of fluoxetine (fluox) into raphe (n=6) or a direct stereotaxic perfusion of BDNF, Wnt2 or 15d-PGJ2 into the hippocampus (n=7). Combined injections were carried out using concentrations selected according to the combination index method of Chou-Talalay.¹⁹ An optimal response was reached with a combination of 50 ng ml⁻¹ BDNF, 1.5 ng ml⁻¹ Wnt2 and 0.25 μ 15d-PGJ2. (a) The miR-16 level (real-time PCR), (b) SERT expression ([³H]-paroxetine binding) and (c) bcl-2 protein expression (western blot analysis) were measured in hippocampus extracts. Control values were obtained in n=9 mice. The values are the means±s.e.m. ^*P<0.01 and ^**P<0.05 vs control. (d) Prozac treatment induces the secretion of S100β, BDNF, Wnt2 and 15d-PGJ2 from raphe serotonergic neurons. These signals relay the action of fluoxetine by downregulating miR-16, which acts as a micromanager in the hippocampal response to SRI antidepressants.