BackgroundThe selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders, but cellular mechanisms underlying the antidepressant effect of FLX remain largely unknown. The generally accepted effect of chronic FLX treatment is increased adult neurogenesis in the hippocampal dentate gyrus. It was recently demonstrated that FLX treatments can reverse the established neuronal maturation of granule cells in the hippocampal dentate gyrus and of gamma-aminobutyric acidergic (GABAergic) interneurons in the basolateral amygdala. However, it is not clear whether this dematuration effect of FLX occurs in other brain regions. Thus, in this study, we used immunohistological analysis to assess the effect of FLX treatment on GABAergic interneurons in the medial frontal cortex (mFC) and reticular thalamic nucleus (RTN).ResultsImmunofluorescence analysis for perineuronal nets (PNNs), which is a marker of neuronal maturation, and for parvalbumin, calretinin, and somatostatin, which are markers for specific GABAergic interneuron type, showed lower number of parvalbumin-positive (+) cells and PNN+/parvalbumin+ cells in the mFC of FLX-treated mice compared to vehicle-treated mice. However, FLX treatment had no effect on the number of cells expressing calretinin and somatostatin in the mFC. In the RTN, the number of PNN+ cells and parvalbumin+ cells was unaltered by FLX treatments. Furthermore, the number of total GABA+ cells and apoptotic cells in the mFC was similar between vehicle- and FLX-treated mice, suggesting that FLX treatment did not induce cell death in this region. Rather, our findings suggest that the decreased number of parvalbumin+ cells in the mFC was due to a decreased expression of parvalbumin proteins in the interneurons.ConclusionsThis study indicates that FLX decreases the levels of parvalbumin, a mature marker of fast-spiking interneurons, and PNNs in parvalbumin+ interneurons in the mFC, suggesting that FLX treatment induces a dematuration of this type of neurons. Induction of a juvenile-like state in fast-spiking inhibitory interneurons in these regions might be involved in the therapeutic mechanism of this antidepressant drug and/or some of its adverse effects.

Adult neurogenesis in the hippocampal subgranular zone (SGZ) and the anterior subventricular zone (SVZ) is regulated by multiple factors, including neurotransmitters, hormones, stress, aging, voluntary exercise, environmental enrichment, learning, and ischemia. Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) modulates adult neurogenesis in the SGZ, the neuronal area that is hypothesized to mediate the antidepressant effects of these substances. Layer 1 inhibitory neuron progenitor cells (L1-INP cells) were recently identified in the adult cortex, but it remains unclear what factors other than ischemia affect the neurogenesis of L1-INP cells. Here, we show that chronic treatment with an SSRI, fluoxetine (FLX), stimulated the neurogenesis of γ-aminobutyric acid (GABA)ergic interneurons from L1-INP cells in the cortex of adult mice. Immunofluorescence and genetic analyses revealed that FLX treatment increased the number of L1-INP cells in all examined cortical regions in a dose-dependent manner. Furthermore, enhanced Venus reporter expression driven by the synapsin I promoter demonstrated that GABAergic interneurons were derived from retrovirally labeled L1-INP cells. In order to assess if these new GABAergic interneurons possess physiological function, we examined their effect on apoptosis surrounding areas following ischemia. Intriguingly, the number of neurons expressing the apoptotic marker, active caspase-3, was significantly lower in adult mice pretreated with FLX. Our findings indicate that FLX stimulates the neurogenesis of cortical GABAergic interneurons, which might have, at least, some functions, including a suppressive effect on apoptosis induced by ischemia.

BackgroundSynaptosomal-associated protein, 25 kDa (SNAP-25) regulates the exocytosis of neurotransmitters. Growing evidence suggests that SNAP-25 is involved in neuropsychiatric disorders, such as schizophrenia, attention-deficit/hyperactivity disorder, and epilepsy. Recently, increases in anxiety-related behaviors and epilepsy have been observed in SNAP-25 knock-in (KI) mice, which have a single amino acid substitution of Ala for Ser187. However, the molecular and cellular mechanisms underlying the abnormalities in this mutant remain unknown.ResultsIn this study, we found that a significant number of dentate gyrus (DG) granule cells was histologically and electrophysiologically similar to immature DG neurons in the dentate gyrus of the adult mutants, a phenomenon termed the “immature DG” (iDG). SNAP-25 KI mice and other mice possessing the iDG phenotype, i.e., alpha-calcium/calmodulin-dependent protein kinase II heterozygous mice, Schnurri-2 knockout mice, and mice treated with the antidepressant fluoxetine, showed similar molecular expression patterns, with over 100 genes similarly altered. A working memory deficit was also identified in mutant mice during a spontaneous forced alternation task using a modified T-maze, a behavioral task known to be dependent on hippocampal function. Chronic treatments with the antiepileptic drug valproate abolished the iDG phenotype and the working memory deficit in mutants.ConclusionsThese findings suggest that the substitution of Ala for Ser187 in SNAP-25 induces the iDG phenotype, which can also be caused by epilepsy, and led to a severe working memory deficit. In addition, the iDG phenotype in adulthood is likely an endophenotype for at least a part of some common psychiatric disorders.