抄録
Antidepressant drugs are widely used to treat mood and anxiety disorders. However, the cellular mechanisms underlying their therapeutic effects and adverse reactions are not well understood. We have shown that chronic treatment with the serotonergic antidepressant fluoxetine causes various changes in physiological functions of granule cells in the hippocampal dentate gyrus in mice. A lower dose of fluoxetine can stabilize serotonergic modulation at the synapse formed by the mossy fiber axon of the granule cell onto the pyramidal cell in the CA3 region. A higher dose of fluoxetine markedly enhances both serotonergic and dopaminergic modulations at the mossy fiber synapse. In addition, higher-dose fluoxetine reverses the state of maturation of the dentate granule cells in adult mice. After treatment with fluoxetine, the granule cell shows immature physiological properties, including higher somatic excitability and reduced frequency facilitation at the mossy fiber synapse. This "dematuration" is induced in a large population of the dentate neurons and is maintained for at least 1 month after withdrawal of fluoxetine. In a mouse model of neuroendocrine dysregulation of mood disorders produced through chronic treatment with corticosterone, the fluoxetine-induced plastic changes in the dentate gyrus are facilitated, and the granule cell dematuration can be induced at a fluoxetine dose producing blood levels comparable to those in patients receiving chronic fluoxetine treatment. Our findings suggest that the fluoxetine-induced plastic changes in the hippocampal dentate gyrus are candidate cellular bases involved in mechanisms of action of antidepressant drugs.
