Abstract
BackgroundSelective serotonin reuptake inhibitors (SSRIs) are widely used to treat mood and anxiety disorders. However, neuronal bases for both beneficial and adverse effects of SSRIs remain poorly understood. We have recently shown that the SSRI fluoxetine can reverse the state of maturation of hippocampal granule cells in adult mice. The granule cell "dematuration" is induced in a large population of granule cells, and greatly changes functional and physiological properties of these cells. Here we show that this unique form of neuronal plasticity is correlated with a distinct change in behavior of mice.ResultsWe chronically treated adult male mice with fluoxetine, and examined its effect on several forms of behavior of mice. During fluoxetine treatments, mice showed a marked increase in day-to-day fluctuations of home cage activity levels that was characterized by occasional switching between hypoactivity and hyperactivity within a few days. This destabilized cage activity was accompanied by increased anxiety-related behaviors and could be observed up to 4 weeks after withdrawal from fluoxetine. As reported previously, the granule cell dematuration by fluoxetine includes a reduction of synaptic facilitation at the granule cell output, mossy fiber, synapse to the juvenile level. Mossy fiber synaptic facilitation examined electrophysiologically in acute hippocampal slices also remained suppressed after fluoxetine withdrawal and significantly correlated with the fluctuation of cage activity levels in individual mice. Furthermore, in mice lacking the 5-HT4 receptor, in which the granule cell dematuration has been shown to be attenuated, fluoxetine had no significant effect on the fluctuation of cage activity levels.ConclusionsOur results demonstrate that the SSRI fluoxetine can induce marked day-to-day changes in activity levels of mice in the familiar environment, and that the dematuration of the hippocampal granule cells is closely associated with the expression of this destabilized behavior. Based on these results, we propose that the granule cell dematuration can be a potential cellular basis underlying switching-like changes in the behavioral state associated with SSRI treatments.
Highlights
Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat mood and anxiety disorders
The home cage activity levels were quite stable throughout the course of experiments (Figure 1A left) except for a gradual small decline as seen in the averaged data (Figure 1B)
In about 2 weeks of treatments, they started showing a marked day-today fluctuation of activity levels (Figure 1E left) that was accompanied by occasional switching from hypoactivity to hyperactivity and vice versa in a few days. To quantify this fluctuation of home cage activity, we calculated the coefficient of variation (CV) of activity levels during the last 2 weeks of the treatments
Summary
Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat mood and anxiety disorders. The change in the state of the granule cell maturation gradually develops over the course of the fluoxetine treatment for a few weeks and is manifested as marked changes in physiological and functional properties of the granule cell that include neuronal excitability, activity-dependent synaptic modifications, and immediate early gene expression [9]. Since this novel form of neuronal plasticity is induced in a large population of the dentate granule cells, it is supposed to have a substantial impact on the operation of hippocampal neuronal circuits and probably on hippocampus-dependent regulation of behaviors. We analyzed changes in behaviors of mice treated with fluoxetine in a regimen that is sufficient for the induction of granule cell dematuration, and examined the association between observed behavioral changes and the granule cell dematuration
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