iPlasticity: Induced juvenile‐like plasticity in the adult brain as a mechanism of antidepressants

Umemori, Juzoh; Winkel, Frederike; Didio, Giuliano; Pou, Maria Llach; Ċastrén, Eero

doi:10.1111/pcn.12683

Cited by 54 publications

(54 citation statements)

References 225 publications

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“…Considering these findings, our results suggest that chronic FLX treatment may induce dematuration of astrocytes, oligodendrocytes, GCs, and FS neurons in the adult hippocampus and mPFC. This may reopen developmental or juvenile‐like states in these cell types as previously proposed for FS neurons in the visual cortex and lateral amygdala …”

Section: Discussionsupporting

confidence: 52%

“…This may reopen developmental or juvenile-like states in these cell types as previously proposed for FS neurons in the visual cortex and lateral amygdala. 10,11,38 Striking similarities in gene expression patterns were observed in mice chronically treated with FLX, several rodent models of neuropsychiatric disorders, and naive infant mice, especially in the hippocampus. GCs in the hippocampal DG of rodent models of these diseases commonly exhibit molecular, morphological, and/or electrophysiological features that are similar to those of naive infant mice.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptomic evidence for immaturity induced by antidepressant fluoxetine in the hippocampus and prefrontal cortex

Hagihara

Ohira

Miyakawa

2019

Neuropsychopharm Rep

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Aims The molecular and cellular mechanisms underlying the antidepressant effects of fluoxetine in the brain are not fully understood. Emerging evidence has led to the hypothesis that chronic fluoxetine treatment induces dematuration of certain types of mature neurons in rodents. These studies have focused on the properties of typical molecular and/or electrophysiological markers for neuronal maturation. Nevertheless, it remains unknown whether dematuration‐related phenomena are present at the genome‐wide gene expression level. Methods Based on the aforementioned hypothesis, we directly compared transcriptome data between fluoxetine‐treated adult mice and those of naive infants in the hippocampus and medial prefrontal cortex (mPFC) to assess similarities and/or differences. We further investigated whether fluoxetine treatment caused dematuration in these brain regions in a hypothesis‐free manner using a weighted gene co‐expression network analysis (WGCNA). Results Gene expression patterns in fluoxetine‐treated mice resembled those in infants in the mPFC and, to a large extent, in the hippocampus. The gene expression patterns of fluoxetine‐treated adult mice were more similar to those of approximately 2‐week‐old infants than those of older mice. WGCNA confirmed that fluoxetine treatment was associated with maturation abnormalities, particularly in the hippocampus, and highlighted respective co‐expression modules for maturity and immaturity marker genes in the hippocampus in response to fluoxetine treatment. Conclusions Our results strongly support the hypothesis that chronic fluoxetine treatment induces dematuration in the adult mouse brain from a transcriptomic standpoint. Detection of discrete transcriptomic regulatory networks related to fluoxetine treatment may help to further elucidate the mechanisms of antidepressant action.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Transcriptomic evidence for immaturity induced by antidepressant fluoxetine in the hippocampus and prefrontal cortex

Hagihara

Ohira

Miyakawa

2019

Neuropsychopharm Rep

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“…Antidepressant-induced dematuration of dentate granule cells and certain types of interneurons in the hippocampus would alter neuronal excitability, morphology, and connectivity, which could gradually improve neuronal information processing and contribute to mood recovery. Consistent with this theory, FLX treatment has been reported to reinstate neural plasticity [28] and promote electrophysiological and functional recovery in the visual cortex of adult amblyopic rats [29]. Furthermore FLX treatment increases expression of brainderived neurotrophic factor in the brain [30,31]; overexpression of brain-derived neurotrophic factor accelerates PV+ cell maturation, which reduces the capacity for cortical neural plasticity [32,33].…”

Section: Discussionmentioning

confidence: 94%

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

Ohira

Hagihara

Miwa

et al. 2019

Preprint

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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.

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“…This suggests that stress causes remodeling of neural circuits to adjust the emotion/cognition (E/C) balance to adapt to stressful environments. In addition to antidepressants, mood stabilizers and atypical antipsychotics also upregulate BDNF and possibly enhance plasticity. These treatments might enhance the recovery from abnormally remodeled neural circuits by this mechanism.…”

Section: Animal Modelsmentioning

confidence: 99%

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

Kato

2019

Psychiatry Clin Neurosci

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Biological studies of bipolar disorder initially focused on the mechanism of action for antidepressants and antipsychotic drugs, and the roles of monoamines (e.g., serotonin, dopamine) have been extensively studied. Thereafter, based on the mechanism of action of lithium, intracellular signal transduction systems, including inositol metabolism and intracellular calcium signaling, have drawn attention. Involvement of intracellular calcium signaling has been supported by genetics and cellular studies. Elucidation of the neural circuits affected by calcium signaling abnormalities is critical, and our previous study suggested a role of the paraventricular thalamic nucleus. The genetic vulnerability of mitochondria causes calcium dysregulation and results in the hyperexcitability of serotonergic neurons, which are suggested to be susceptible to oxidative stress. Efficacy of anticonvulsants, animal studies of candidate genes, and studies using induced pluripotent stem cell‐derived neurons have suggested a relation between bipolar disorder and the hyperexcitability of neurons. Recent genetic findings suggest the roles of polyunsaturated acids. At the systems level, social rhythm therapy targets circadian rhythm abnormalities, and cognitive behavioral therapy may target emotion/cognition (E/C) imbalance. In the future, pharmacological and psychosocial treatments may be combined and optimized based on the biological basis of each patient, which will realize individualized treatment.

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iPlasticity: Induced juvenile‐like plasticity in the adult brain as a mechanism of antidepressants

Cited by 54 publications

References 225 publications

Transcriptomic evidence for immaturity induced by antidepressant fluoxetine in the hippocampus and prefrontal cortex

Transcriptomic evidence for immaturity induced by antidepressant fluoxetine in the hippocampus and prefrontal cortex

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

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

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