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

Abstract

The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants (AD), including selective serotonin reuptake inhibitors (SSRI), function by gradually improving information processing within these networks. AD have been shown to induce a state of juvenile‐like plasticity comparable to that observed during developmental critical periods: Such critical‐period‐like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals. We have coined this drug‐induced state of juvenile‐like plasticity ‘iPlasticity.’ A combination of iPlasticity induced by chronic SSRI treatment together with training, rehabilitation, or psychotherapy improves symptoms of neuropsychiatric disorders and issues underlying the developmentally or genetically malfunctioning networks. We have proposed that iPlasticity might be a critical component of AD action. We have demonstrated that iPlasticity occurs in the visual cortex, fear erasure network, extinction of aggression caused by social isolation, and spatial reversal memory in rodent models. Chronic SSRI treatment is known to promote neurogenesis and to cause dematuration of granule cells in the dentate gyrus and of interneurons, especially parvalbumin interneurons enwrapped by perineuronal nets in the prefrontal cortex, visual cortex, and amygdala. Brain‐derived neurotrophic factor (BDNF), via its receptor tropomyosin kinase receptor B, is involved in the processes of synaptic plasticity, including neurogenesis, neuronal differentiation, weight of synapses, and gene regulation of synaptic formation. BDNF can be activated by both chronic SSRI treatment and neuronal activity. Accordingly, the BDNF/tropomyosin kinase receptor B pathway is critical for iPlasticity, but further analyses will be needed to provide mechanical insight into the processes of iPlasticity.

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

“…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 …”

“…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.…”

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

“…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].…”

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

“…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.…”