Homing in on the therapeutic mechanisms of commonly used antidepressants

November 11, 2015 | Ryan Logan PhD

Credit: Freeze fracture electron micrograph of a synapse showing the pre-synaptic terminal (center right) filled with vesicles of neurotransmitter (blue) making contact with the post-synaptic target cell (center left). Credit: Dr David Furness / Wellcome Images

With the advent of new technology, comes a better understanding of the brain and the hope for novel treatments and medications with improved specificity and therapeutic efficacy. The most widely used class of antidepressants is selective serotonin reuptake inhibitors (SSRIs), which block the reuptake of serotonin from the presynaptic terminal, allowing for accumulation of serotonin within the synaptic cleft. Chronic treatment with SSRIs also induces neurogenesis of mature granule cells in the dentate gyrus of the hippocampus which are thought to contribute to the antidepressant response. Mature granule cells express high levels of the serotonin receptor, 5HT1A. These receptors are intimately involved in anxiety, depression, and response to antidepressants.

Many of the pioneering studies demonstrating a role for hippocampal neurogenesis in the antidepressant response to SSRIs come from Dr. René Hen’s laboratory at Columbia University. A new study from his group investigated the involvement of serotonin receptors on granule cells of the dentate gyrus in regulating the anxiolytic behavioral response to the SSRI, fluoxetine (Prozac). The researchers used multiple approaches to target 5HT1A serotonin receptors specifically within granule cells of the hippocampus.

Similar to humans, only chronic, but not acute, fluoxetine treatment reverses anxiety and depression related behaviors in mice. However, serotonin receptor knockdown mice, with a 90% reduction in serotonin receptors failed to respond to chronic fluoxetine treatment during behavioral assays of anxiety, despair, and the ability to feel pleasure. Viral-mediated knockdown of serotonin receptors in granule cells of the dentate gyrus also resulted in a failed antidepressant response in mice, further supporting the notion that serotonin receptors specifically on these cells in the hippocampus are necessary for the antidepressant response to fluoxetine.

Chronic treatment with fluoxetine promotes the hippocampal proliferation of neural precursor cells and the maturation of young granule cells, yet it was unknown whether either ‘young’ or mature cells—or both—were contributing to the behavioral response to fluoxetine. Using a floxed-cre approach the researchers controlled knockdown of serotonin receptors at certain time-points during fluoxetine treatment. Tamoxifen-induced knockdown of serotonin receptors in ‘young’ hippocampal cells failed to have any anxiolytic or antidepressant effect in related behavioral assays, suggesting that mature cells are necessary while immature cells are not, for the fluoxetine response. These findings were corroborated by showing that serotonin receptor rescue in the dentate gyrus restored the behavioral responses to fluoxetine. The researchers went on to demonstrate that mature dentate gyrus granule cells also mediated increased hippocampal neurogenesis, expression of neural growth factors, and reduced corticosterone response to stress following chronic fluoxetine treatments.

Thus, the anxiolytic and antidepressant effects of fluoxetine seem to be primarily acting via serotonin receptors expressed specifically within mature granule cells of the dentate gyrus. A better understanding of the precise mechanisms of SSRI therapeutic action provides the basis for future studies to investigate the underlying reasons for differential therapeutic response of patient populations. These findings may provide the basis for more targeted treatments of anxiety and depression disorders.

Publication

  1. Samuels BA et al. (2015) 5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response. Nature Neuroscience 18:1606-1616. doi: 10.1038/nn.4116

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