Abstract
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) used to treat mood and anxiety disorders. Chronic treatment with this antidepressant drug is thought to favor functional recovery by promoting structural and molecular changes in several forebrain areas. At the synaptic level, chronic fluoxetine induces an increased size and density of dendritic spines and an increased ratio of GluN2A over GluN2B N-methyl-D-aspartate (NMDA) receptor subunits. The “maturation”-promoting molecular changes observed after chronic fluoxetine should also induce structural remodeling of the neuronal dendritic arbor and changes in the synaptic responses. We treated adult rats with fluoxetine (0.7 mg/kg i.p. for 28 days) and performed a morphometric analysis using Golgi stain in limbic and nonlimbic cortical areas. Then, we focused especially on the auditory cortex, where we evaluated the dendritic morphology of pyramidal neurons using a 3-dimensional reconstruction of neurons expressing mRFP after in utero electroporation. With both methodologies, a shortening and decreased complexity of the dendritic arbors was observed, which is compatible with an increased GluN2A over GluN2B ratio. Recordings of extracellular excitatory postsynaptic potentials in the auditory cortex revealed an increased synaptic response after fluoxetine and were consistent with an enrichment of GluN2A-containing NMDA receptors. Our results confirm that fluoxetine favors maturation and refinement of extensive cortical networks, including the auditory cortex. The fluoxetine-induced receptor switch may decrease GluN2B-dependent toxicity and thus could be applied in the future to treat neurodegenerative brain disorders characterized by glutamate toxicity and/or by an aberrant network connectivity.
Highlights
Selective serotonin reuptake inhibitors (SSRI) such as fluoxetine, used in chronic antidepressant treatment, induce adaptive rearrangements in the central nervous system that are not fully characterized
We had previously shown that repetitive fluoxetine treatment augmented the spine density and the number of mature, mushroomtype spines and favored GluN2A-containing NMDARs and GluA2containing α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPA-Rs) (Ampuero et al, 2010; Ampuero et al, 2013; Rubio et al, 2013)
E.g., the prelimbic cortex (PrL) and retrosplenial granular b cortex (RSGb), a decrease in the total dendritic length after fluoxetine treatment was observed, and this resulted from a reduction in the basal dendritic lengths in layer II–III neurons of the PrL cortex and in layer V neurons
Summary
Selective serotonin reuptake inhibitors (SSRI) such as fluoxetine, used in chronic antidepressant treatment, induce adaptive rearrangements in the central nervous system that are not fully characterized. Fluoxetine induces an enlargement of dendritic spines and increased spine density in several forebrain regions (Hajszan et al, 2005; Guirado et al, 2009; Ampuero et al, 2010; Kitahara et al, 2016) In adult rats, this is associated with a switch of synaptic glutamate receptor subunits favoring an enrichment of NMDA receptors (NMDA-Rs) containing preferentially GluN2A over GluN2B subunits (Ampuero et al, 2010; Rubio et al, 2013; Beshara et al, 2016), a switch consistent with synaptic maturation (Paoletti et al, 2013). Our results indicate that fluoxetine induces structural and functional adaptations compatible with increased network maturation These properties of fluoxetine could be useful in the treatment of diseases characterized by altered GluN2B over GluN2A ratios and the associated growth of aberrant dendritic arbors and/or of diseases characterized by NMDA-R-dependent toxicity due to GluN2Bdependent calcium overload
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