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

Juzoh Umemori, Frederike Winkel, Giuliano Didio, Maria Llach Pou, Eero Castrén, Juzoh Umemori, Frederike Winkel, Giuliano Didio, Maria Llach Pou, Eero Castrén

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.

Keywords: brain-derived neurotrophic factor/tropomyosin kinase receptor B; dematuration; neurogenesis; neuronal plasticity; parvalbumin/perineuronal nets.

© 2018 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

Figures

Figure 1
Figure 1
Concept of iPlasticity. Amy, amygdala; BDNF, brain‐derived neurotrophic factor; ChABC, chondroitinase ABC; DG, dentate gyrus; GC, granule cell; HNK, hydroxynorketamine; HP, hippocampus; PFC, prefrontal cortex; PV/PNN, parvalbumin/ perineuronal nets; TrkB, tropomyosin kinase receptor B.
Figure 2
Figure 2
Model of dematuration and adult neurogenesis in the dentate gyrus (DG) by chronic selective serotonin reuptake inhibitors (SSRI) treatment. The upper section indicates expression markers of each neuron state.102, 103 In the middle section, a mature neuron change to an immature state by dematuration after chronic SSRI treatment or electroconvulsive stimulation (ECS). In the bottom section, chronic SSRI treatment or environmental enrichment (EE) promote the proliferation of progenitor granule cells in the DG and rapid maturation of young adult‐born cells and integration into the DG. Finally, the matured adult‐born cell is functionally similar to other mature cells. The picture is combined and modified from Zhang and Jiao102 and Segi‐Nishida.103 DCX, doublecortin; ML, molecular layer; GL, granule layer; PSA‐NCAM, polysialic acid neural cell adhesion molecule; SGZ, subgranular zone. Copyright © 2017 Segi‐Nishida. Copyright © 2015 Juan Zhang and Jianwei Jiao.
Figure 3
Figure 3
Dematuration of parvalbumin (PV)/perineuronal nets (PNN) interneurons. PNN surround synaptic boutons on neuronal soma and proximal dendrites and consist of chondroitin sulfate proteoglycans (CSPG) assembled on the hyaluronan scaffold of PV interneurons. The development of PNN is controlled by synaptic activity and their formation terminates the critical period of synaptic plasticity, consolidating the neuronal network. CSPG has a unique geometric structure of polygonal mesh shapes with the number of vertices varying from three to nine. Sizes of the mesh vary.151 A reduction in PV (green) and PNN (blue) expression is associated with a plastic and immature network observed in iPlasticity by chronic SSRI treatment.
Figure 4
Figure 4
Brain‐derived neurotrophic factor (BDNF)/tropomyosin kinase receptor B (TrkB) pathway. BDNF is synthesized as a precursor protein (pro‐BDNF) that is proteolytically processed into mature BDNF by intracellular proteases and/or extracellular proteases.159, 160, 161 Synthesis, release, and action of BDNF are regulated by neuronal activity. BDNF mRNA increases after neuron depolarization162 and BDNF levels are mediated by calcium‐calmodulin‐dependent protein kinases (CaMK).163 TrkB is a tyrosine kinase membrane protein highly expressed in both presynaptic axons and postsynaptic densities.164, 165, 166 TrkB activation promotes spine formation, neuronal survival, and long‐term potentiation.167, 168, 169, 170, 171 TrkB consists of the following three main domains: an extracellular domain where the ligand (usually BDNF) binds, a transmembrane domain, and a cytosolic domain, which contains the catalytic sites that are responsible for a transphosphorylation reaction.172 Binding of BDNF to the recognition site increases its affinity for the TrkB monomer, stabilizing to form a TrkB dimer.173 This dimerization activates the catalytic sites, and each TrkB phosphorylates the other on specific tyrosine residues (Y706).174 Secondary messenger molecules (such as sarc homology containing [Shc] and phospholipase C gamma [PLCγ]) bind to the phospho‐tyrosines in positions 515 (Y515) and 816 (Y816) and activate the Ras/Erk and PIP3/Ca+2 dependent pathways, respectively. The latter pathway leads to activation of protein kinase C (PKC) and eventually to the phosphorylation of cyclic AMP response element binding protein (CREB).175 CREB in turn induces gene expression involved in neuroplasticity.176, 177, 178, 179, 180, 181, 182 Neuronal activation and high‐frequency stimulation facilitate the localization of TrkB from intracellular pools to the cell surface, requiring a Ca+2 influx.183 Akt, cellular homolog of murine thymoma virus akt8 oncogene; CBP, CREB‐binding protein; ERK, extracellular signal‐regulated kinase; P, phosphorylation.

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