Fluoxetine-induced dematuration of hippocampal neurons and adult cortical neurogenesis in the common marmoset

Abstract

word count: 239 words Article body word count: 3181 words Figures: 5 Tables: 2 Supplemental information: 6 figures and 0 tables. AbstractThe selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders. Chronic FLX treatment reportedly induces cellular responses in the brain, including increased adult hippocampal and cortical neurogenesis and reversal of neuron maturation in the hippocampus, amygdala, and cortex. However, because most previous studies have used rodent models, it remains unclear whether these FLX-induced changes occur in the primate brain. To evaluate the effects of FLX in the primate brain, we used immunohistological methods to assess neurogenesis and the expression of neuronal maturity markers following chronic FLX treatment (3 mg/kg/day for 4 weeks) in adult marmosets (n = 3 per group). We found increased expression of doublecortin and calretinin, markers of immature neurons, in the hippocampal dentate gyrus of FLX-treated marmosets.Further, FLX treatment reduced parvalbumin expression and the number of neurons with perineuronal nets, which indicate mature fast-spiking interneurons, in the hippocampus, but not in the amygdala or cerebral cortex. We also found that FLX treatment increased the generation of cortical interneurons; however, significant upregulation of adult hippocampal neurogenesis was not observed in FLX-treated marmosets. These results suggest that dematuration of hippocampal neurons and increased cortical neurogenesis may play roles in FLX-induced effects and/or side effects. Our results are consistent with those of previous studies showing hippocampal dematuration and increased cortical neurogenesis in FLX-treated rodents. In contrast, FLX did not affect hippocampal neurogenesis or dematuration of interneurons in the amygdala and cerebral cortex.

Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala

“…Indeed, it is conceivable that the impairment of reward processing and dysregulation of underlying molecular mechanisms would be less severe or even absent if the treatment lasted for a shorter period of time. This would be in agreement with recent findings illustrating that fluoxetine hinders neurogenesis after 6 and 9, but not after 3 weeks of intake (Ohira, Hagihara, Miwa, Nakamura, & Miyakawa, 2019). Still, the length of the applied treatment may not be an exclusive explanation of the discrepancies in the literature, as deteriorating effects of fluoxetine have been reported after chronic drug administration significantly shorter than the one used in the present research (Dringenberg, Branfield Day, & Choi, 2014; Eisenreich, Greene, & Szalda‐Petree, 2017; Flores‐Ramirez et al, 2019; Frick, Bernardez‐Vidal, Hocht, Zanutto, & Rapanelli, 2015; Sharp et al, 2019; Takahashi et al, 2005).…”

Understanding the Real State of Human Adult Hippocampal Neurogenesis From Studies of Rodents and Non-human Primates

“…These improved immunohistochemical techniques revealed a substantial number of DCX+ cells in the human DG. A subpopulation of DCX+ cells were positive for PH3, Prox1, PSA-NCAM, calbindin, and calretinin, but they were often found in the upper and middle parts of the GCL in addition to the SGZ, which appears to resemble granule cells undergoing dematuration, as reported previously (Hagihara et al, 2019;Ohira et al, 2019). Persistent neurogenesis, which is shown by the presence of Nestin+/Sox2+/Ki67+ neural progenitors, DCX+/PCNA+ neuroblasts, and DCX+ immature neurons, was also reported in older adults and to a lesser extent, in Alzheimer disease patients (Tobin et al, 2019).…”

“…Furthermore, a recent report has shown that an increase in DCX+ dentate granule cells without an increase in neuronal production is induced by fluoxetine treatment in the common marmoset, which suggests that mature granule cells are able to re-express INMs, which is a phenomenon called dematuration (Ohira et al, 2019).…”

Long-term effects of early treatment with SSRIs on cognition and brain development in individuals with 22q11.2 deletion syndrome

“…Overall, these cortical morphometry findings align with previous studies showing the increase of hippocampal volume and thickening of frontal and cingulate regions after SSRIs treatment 34,35 , suggesting that enhanced neurotrophic synthesis may reverse processes of cortical thinning and atrophy even in deletion carriers with psychotic symptoms [54][55][56] . Therefore, long-term treatment with SSRIs seems to have a selective effect on intellectual functioning and the maturation of a specific network comprising frontal and limbic brain regions.…”