Summary It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo . We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery.
It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We found that both typical and fast-acting antidepressants bind to a cholesterol interaction motif in the BDNF receptor TRKB, a known mediator of neuronal plasticity and antidepressant responses. Cholesterol stabilized a cross-shaped configuration of TRKB transmembrane domain dimers and prolonged TRKB cell surface expression and activation by BDNF. Mutation of the TRKB cholesterol interaction site or cholesterol depletion by pravastatin impaired BDNF-mediated plasticity and cellular and behavioral responses to antidepressants in vitro and in vivo . We suggest that binding to and facilitation of TRKB activity is the common mechanism for antidepressant action, and propose a framework for how molecular effects of antidepressants are translated into clinical mood recovery.
Perineuronal nets (PNNs) are an extracellular matrix structure rich in chondroitin sulfate proteoglycans (CSPGs), which preferentially encase parvalbumin-containing (PV + ) interneurons. PNNs restrict cortical network plasticity but the molecular mechanisms involved are unclear. We found that reactivation of ocular dominance plasticity in the adult visual cortex induced by chondroitinase ABC (chABC)-mediated PNN removal requires intact signaling by the neurotrophin receptor TRKB in PV + neurons. Additionally, we demonstrate that chABC increases TRKB phosphorylation (pTRKB), while PNN component aggrecan attenuates brain-derived neurotrophic factor (BDNF)-induced pTRKB in cortical neurons in culture. We further found that protein tyrosine phosphatase σ (PTPσ, PTPRS), receptor for CSPGs, interacts with TRKB and restricts TRKB phosphorylation. PTPσ deletion increases phosphorylation of TRKB in vitro and in vivo in male and female mice, and juvenile-like plasticity is retained in the visual cortex of adult PTPσ-deficient mice (PTPσ +/− ). The antidepressant drug fluoxetine, which is known to promote TRKB phosphorylation and reopen critical period-like plasticity in the adult brain, disrupts the interaction between TRKB and PTPσ by binding to the transmembrane domain of TRKB. We propose that both chABC and fluoxetine reopen critical period-like plasticity in the adult visual cortex by promoting TRKB signaling in PV + neurons through inhibition of TRKB dephosphorylation by the PTPσ-CSPG complex. SIGNIFICANCE STATEMENT Critical period-like plasticity can be reactivated in the adult visual cortex through disruption of perineuronal nets (PNNs) by chondroitinase treatment, or by chronic antidepressant treatment. We now show that the effects of both chondroitinase and fluoxetine are mediated by the neurotrophin receptor TRKB in parvalbumin-containing (PV + ) interneurons. We found that chondroitinase-induced visual cortical plasticity is dependent on TRKB in PV + neurons. Protein tyrosine phosphatase σ (PTPσ, PTPRS), a receptor for PNNs, interacts with TRKB and inhibits its phosphorylation, and chondroitinase treatment or deletion of PTPσ increases TRKB phosphorylation. Antidepressant fluoxetine disrupts the interaction between TRKB and PTPσ, thereby increasing TRKB phosphorylation. Thus, juvenile-like plasticity induced by both chondroitinase and antidepressant treatment is mediated by TRKB activation in PV + interneurons.
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.
The in utero exposure to common chemical stressors, environmental pollutant methylmercury and antidepressant fluoxetine, results in behavioral impairments persistent into adulthood. Modulation of critical periods in brain development may alter proper network formation and lastingly impair brain function. To investigate whether early-life stressors can modulate critical periods, we analyzed the development of parvalbumin (PV) and perineuronal nets (PNNs) in the dentate gyrus and CA1 area of the hippocampus and the basolateral amygdala in mice perinatally exposed to either fluoxetine or methylmercury. The number of PV and PNN neurons, and PV intensity, were analyzed by fluorescent immunohistochemistry at the postnatal ages P17 (ongoing critical period) and P24 (closing critical period). The exposure to fluoxetine did not affect the number of PV cells and PV intensity but decreased PNN formation around the cells at P17 and P24 in all tissues. In contrast, perinatal methylmercury inhibited the development of PV interneurons and PV expression at P17 only, but at P24 these parameters were restored. Methylmercury strongly increased PNN formation from P17 to P24 in the amygdala only. We suggest that perinatal fluoxetine and methylmercury might delay the closure and the onset, respectively, of the critical periods in the amygdala and hippocampus.
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