抄録
The dentate gyrus of the hippocampus has been implicated in behavioral effects of antidepressant drugs including selective serotonin reuptake inhibitors (SSRIs). The mossy fiber (MF) is the sole output of dentate granule cells and thus plays a pivotal role in regulation of hippocampal neuronal activity by the dentate gyrus. To test possible involvement of modification of the MF synapse in behavioral changes caused by SSRIs, we examined effects of chronic oral administration of fluoxetine, a widely used SSRI, on behaviors and the MF synaptic transmission in adult mice. Fluoxetine had multiple effects on behaviors and the MF synaptic transmission in a dose-dependent manner. At a lower dose, the fluoxetine treatment reduced activity of mice in a novel environment and affected modulation of the MF synaptic transmission by serotonin without noticeable effects on the synaptic transmission itself. At higher doses, however, it markedly increased fluctuation of home cage activity and anxiety-related behaviors, and also greatly reduced the large synaptic facilitation that is a characteristic of the mature MF synapse. This synaptic change was well correlated with the behavioral changes. In the dentate gyrus of mice treated with the higher dose of fluoxetine, expression of calbindin, a marker for the mature granule cells, was significantly reduced. These results indicate that fluoxetine at high doses can disrupt the maturation state of the dentate gyrus and the MF synaptic transmission in adult mice, which may underlie the destabilized behavior in the treated mice. [J Physiol Sci. 2008;58 Suppl:S35]
