The serotonin transporter (SERT) regulates transmitter signaling by clearance of serotonin from the extracelluar space and serves as the primary target for the serotonin reuptake inhibitors (SRIs), which are the most widely prescribed antidepressants. SRIs have been suggested to improve symptoms in depression and anxiety disorders via enhancement of hippocampal neurogenesis. However, SERT null mutant mice, although they lack serotonin clearance, have been shown to exhibit increases in anxiety-like behavior. Based on this, we hypothesized that this altered phenotype would be associated with reduced hippocampal neurogenesis in adult mice with constitutive reductions in SERT expression. In the present study, we assessed the proliferation new neurons in the subgranular zone of the hippocampus in 18 month-old SERT deficient mice. Behavior in these mice was previously reported using the elevated plus maze and free choice exploration test and significant increases in anxiety-like behavior in both paradigms were detected in aging SERT-/- mice.
In the present study, mice were sacrificed 24 h after BrdU (4 × 75 mg/kg) to label newly generated cells using immunocytochemistry. All confocal image analysis and cell counting were conducted by counting individual cells in 1μm z-stacks excluding the uppermost and lowermost planes across the entire subgranular zone in every 12th section by an investigator blind to the genotypes of the mice. When these data were combined with our previous data collected 28 d after BrdU and normalized to mean values for SERT+/+ mice at each time, we observed an overall statistically significant difference in cell numbers as a function of genotype [F(2,27)=0.99; p<0.01]. At 24 h post-BrdU, cellular proliferation in SERT-/- mice was significantly decreased by 30% compared to SERT+/+ mice (p<0.001). A nonsignificant 15% reduction in BrdU-labeled cells was observed in SERT+/- mice. A 15% reduction in newly differentiated neurons was also observed in SERT-/- mice at 28 d post-BrdU as determined by counting BrdU-NeuN double-labeled cells. Together, these data suggest that reductions in SERT expression are associated with decreases in the proliferation and survival of adult hippocampal neurons in aging mice and that this might partly underlie increased anxiety-like behavior in these animals, which persists into older ages.