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BACKGROUND: Brain recovery mechanisms after injuries like aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI) involve brain plasticity, synaptic regeneration, and neuroinflammation. We hypothesized that serum levels of the p75 neurotrophic receptor (p75NTR) and associated signaling proteins, as well as differentially expressed (DE) microRNAs, could predict recovery outcomes irrespective of injury type. METHODS: A prospective patient cohort with ischemic stroke (IS, n = 30), aneurysmal subarachnoid hemorrhage (aSAH, n = 31), and traumatic brain injury (TBI, n = 13) were evaluated (total n = 74). Serum samples were collected at two post-injury intervals (early: 1-3 days, late: 4-8 days), and outcomes were assessed after three months using the modified Rankin Scale (mRS), categorizing outcomes as favorable (mRS 0-3) or unfavorable (mRS 4-6). Six proteins were measured using ELISAs: p75NTR, NGF, sortilin, IL1ß, TNFα, and cyclophilin. DE microRNAs were identified using DESeq2, and their target genes were predicted. Serum molecules between patients with differing outcomes were compared using a Kolmogorov-Smirnov test, 2-tailed t-test and multivariate linear discriminant analysis (LDA). RESULTS: Favorable (n = 46) and unfavorable (n = 28) outcome cohorts were balanced with age and sex (p = 0.25 and 0.63). None of the studied proteins correlated with age. Combinatory LDA of the six protein biomarkers indicated strong prognostic value for favorable outcomes (OR 2.09; AUC = 70.3%, p = 0.0058). MicroRNA expression changes over time were identified in the aSAH, TBI, and IS groups (p < 0.05, FDR corrected). Twenty-three microRNAs were commonly DE across all brain injury groups when comparing favorable and unfavorable outcomes (p < 0.05). LDA of four microRNAs targeting the studied proteins showed high prognostic accuracy (OR 11.7; AUC = 94.1%, p = 0.016). CONCLUSIONS: The combined prognostic microRNA and protein biomarker models demonstrated accurate outcome prognostication across diverse injury types, implying the presence of a common recovery mechanism. DE microRNAs were found to target the studied molecules, suggesting a potential mechanistic role in recovery. Further investigation is warranted to study these molecules in prognostication, as well as therapeutic targets for enhancing recovery.
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Major depressive disorder (MDD) is a highly prevalent psychiatric disorder and a leading cause of disability worldwide. Brain-derived neurotrophic factor (BDNF), a signaling protein responsible for promoting neuroplasticity, is highly expressed in the central nervous system but can also be found in the blood. Since impaired brain plasticity is considered a cornerstone in the pathophysiology of MDD, measurement of BDNF in blood has been proposed as a potential biomarker in MDD. The aim of our study is to systematically review the literature for the effects of antidepressant treatments on blood BDNF levels in MDD and the suitability of blood BDNF as a biomarker for depression severity and antidepressant response. We searched Pubmed® and Cochrane library up to March 2024 in a systematic manner using Medical Subject Headings (MeSH). The search resulted in a total of 42 papers, of which 30 were included in this systematic review. Generally, we found that patients with untreated MDD have a lower blood BDNF level than healthy controls. Antidepressant treatments increase blood BDNF levels, and more evidently after pharmacological than non-pharmacological treatment. Neither baseline nor change in the blood BDNF level correlates with depression severity or treatment outcome, which undermines its use as a biomarker in MDD. Our review also highlights the importance of considering factors influencing the accuracy and reproducibility of BDNF measurements. We summarize considerations to help obtain more robust blood BDNF values and compile a list of recommendations to help streamline assessment of blood BDNF levels in future studies.
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BACKGROUND: Diverse antidepressants were recently described to bind to TrkB and drive a positive allosteric modulation of endogenous BDNF. Although neurotrophins such as BDNF can bind to the p75 neurotrophin receptor (p75NTR), their precursors are the high affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely opposite physiological changes, TrkB and p75NTR feature a cross-like conformation dimer and carry a cholesterol-recognition and alignment consensus in the transmembrane domain. Since such qualities were found crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR. METHODS: ELISA-based binding assay and NMR spectroscopy were accomplished to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to address whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase-dependent p75NTR proteolysis, and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75KO mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verifying how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male WT mice and rats. RESULTS: Antidepressants were found binding to p75NTR, FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes. CONCLUSION: We thus hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain ability for remodeling.
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TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the receptor for brain-derived neurotrophic factor (BDNF) and is a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding of the structure and function of TrkB, including its transmembrane domain (TMD). TrkB interacts with membrane cholesterol, which bidirectionally regulates TrkB signaling. Additionally, TrkB has recently been recognized as a binding target of antidepressant drugs. A variety of different antidepressants, including typical and rapid-acting antidepressants, as well as psychedelic compounds, act as allosteric potentiators of BDNF signaling through TrkB. This suggests that TrkB is the common target of different antidepressant compounds. Although more research is needed, current knowledge suggests that TrkB is a promising target for further drug development.
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Glicoproteínas de Membrana , Receptor trkB , Humanos , Receptor trkB/metabolismo , Receptor trkB/química , Animais , Domínios Proteicos , Transdução de Sinais , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/química , Antidepressivos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/químicaRESUMO
Acute brain injuries (ABIs) pose a substantial global burden, demanding effective prognostic indicators for outcomes. This study explores the potential of urinary p75 neurotrophin receptor (p75NTR) concentration as a prognostic biomarker, particularly in relation to unfavorable outcomes. The study involved 46 ABI patients, comprising sub-cohorts of aneurysmal subarachnoid hemorrhage, ischemic stroke, and traumatic brain injury. Furthermore, we had four healthy controls. Samples were systematically collected from patients treated at the University Hospital of Turku between 2017 and 2019, at early (1.50 ± 0.70 days) and late (9.17 ± 3.40 days) post-admission time points. Urinary p75NTR levels, measured by ELISA and normalized to creatinine, were compared against patients' outcomes using the modified Rankin Scale (mRS). Early urine samples showed no significant p75NTR concentration difference between favorable and unfavorable mRS groups. In contrast, late samples exhibited a statistically significant increase in p75NTR concentrations in the unfavorable group (p = 0.033), demonstrating good prognostic accuracy (AUC = 70.9%, 95% CI = 53-89%, p = 0.03). Assessment of p75NTR concentration changes over time revealed no significant variation in the favorable group (p = 0.992) but a significant increase in the unfavorable group (p = 0.009). Moreover, p75NTR concentration was significantly higher in ABI patients (mean ± SD 40.49 ± 28.83-65.85 ± 35.04 ng/mg) compared to healthy controls (mean ± SD 0.54 ± 0.44 ng/mg), irrespective of sampling time or outcome (p < 0.0001). In conclusion, late urinary p75NTR concentrations emerged as a potential prognostic biomarker for ABIs, showing increased levels associated with unfavorable outcomes regardless of the specific type of brain injury. While early samples exhibited no significant differences, the observed late increases emphasize the time-dependent nature of this potential biomarker. Further validation in larger patient cohorts is crucial, highlighting the need for additional research to establish p75NTR as a reliable prognostic biomarker across various ABIs. Additionally, its potential role as a diagnostic biomarker warrants exploration.
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BACKGROUND: The effects of the selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressant treatment, have been proposed to be affected, at least in part, by the living environment. Since the quality of the environment depends not only on its objective features, but also on the subjective experience, we hypothesized that the latter plays a key role in determining SSRI treatment outcome. METHODS: We chronically administered the SSRI fluoxetine to two groups of adult CD-1 male mice that reportedly show distinct subjective experiences of the environment measured as consistent and significantly different responses to the same emotional and social stimuli. These distinct socioemotional profiles were generated by rearing mice either in standard laboratory conditions (SN) or in a communal nest (CN) where three dams breed together their offspring, sharing caregiving behavior. RESULTS: At adulthood, CN mice displayed higher levels of agonistic and anxiety-like behaviors than SN mice, indicating that they experience the environment as more socially challenging and potentially dangerous. We then administered fluoxetine, which increased offensive and anxious response in SN, while producing opposite effects in CN mice. BDNF regulation was modified by the treatment accordingly. LIMITATIONS: Subjective experience in mice was assessed as behavioral response to the environment. CONCLUSIONS: These results show that the subjective experience of the environment determines fluoxetine outcome. In a translational perspective, our findings suggest considering not only the objective quality, but also the subjective appraisal, of the patient's living environment for developing effective personalized therapeutic approaches in psychiatry.
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Antidepressivos , Fluoxetina , Adulto , Camundongos , Masculino , Animais , Humanos , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Ansiedade , Resultado do TratamentoRESUMO
We begin by summarizing several examples of antidepressants whose therapeutic actions begin when they encounter their targets in the cytoplasm or in the lumen of an organelle. These actions contrast with the prevailing view that most neuropharmacological actions begin when drugs engage their therapeutic targets at extracellular binding sites of plasma membrane targets-ion channels, receptors, and transporters. We review the chemical, pharmacokinetic, and pharmacodynamic principles underlying the movements of drugs into subcellular compartments. We note the relationship between protonation-deprotonation events and membrane permeation of antidepressant drugs. The key properties relate to charge and hydrophobicity/lipid solubility, summarized by the parameters LogP, pKa, and LogDpH7.4. The classical metric, volume of distribution (Vd), is unusually large for some antidepressants and has both supracellular and subcellular components. A table gathers structures, LogP, PKa, LogDpH7.4, and Vd data and/or calculations for most antidepressants and antidepressant candidates. The subcellular components, which can now be measured in some cases, are dominated by membrane binding and by trapping in the lumen of acidic organelles. For common antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs), the target is assumed to be the eponymous reuptake transporter(s), although in fact the compartment of target engagement is unknown. We review special aspects of the pharmacokinetics of ketamine, ketamine metabolites, and other rapidly acting antidepressants (RAADs) including methoxetamine and scopolamine, psychedelics, and neurosteroids. Therefore, the reader can assess properties that markedly affect a drug's ability to enter or cross membranes-and therefore, to interact with target sites that face the cytoplasm, the lumen of organelles, or a membrane. In the current literature, mechanisms involving intracellular targets are termed "location-biased actions" or "inside-out pharmacology". Hopefully, these general terms will eventually acquire additional mechanistic details.
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Ketamina , Antidepressivos/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina , Norepinefrina/metabolismo , Organelas/metabolismoRESUMO
Brain-derived neurotrophic factor (BDNF) acting upon its receptor Neurotrophic tyrosine kinase receptor 2 (NTRK2, TRKB) plays a central role in the development and maintenance of synaptic function and activity- or drug-induced plasticity. TRKB possesses an inverted cholesterol recognition and alignment consensus sequence (CARC), suggesting this receptor can act as a cholesterol sensor. We have recently shown that antidepressant drugs directly bind to the CARC domain of TRKB dimers, and that this binding as well as biochemical and behavioral responses to antidepressants are lost with a mutation in the TRKB CARC motif (Tyr433Phe). However, it is not clear if this mutation can also compromise the receptor function and lead to behavioral alterations. Here, we observed that Tyr433Phe mutation does not alter BDNF binding to TRKB, or BDNF-induced dimerization of TRKB. In this line, primary cultures from embryos of heterozygous Tyr433Phe mutant mice (hTRKB.Tyr433Phe) are responsive to BDNF-induced activation of TRKB, and samples from adult mice do not show any difference on TRKB activation compared to wild-type littermates (TRKB.wt). The behavioral phenotype of hTRKB.Tyr433Phe mice is indistinguishable from the wild-type mice in cued fear conditioning, contextual discrimination task, or the elevated plus maze, whereas mice heterozygous to BDNF null allele show a phenotype in context discrimination task. Taken together, our results indicate that Tyr433Phe mutation in the TRKB CARC motif does not show signs of loss-of-function of BDNF responses, while antidepressant binding to TRKB and responses to antidepressants are lost in Tyr433Phe mutants, making them an interesting mouse model for antidepressant research.
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Fator Neurotrófico Derivado do Encéfalo , Receptor trkB , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Receptor trkB/metabolismo , Antidepressivos/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Mutação/genéticaRESUMO
Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.
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Alucinógenos , Humanos , Alucinógenos/farmacologia , Serotonina , Receptor 5-HT2A de Serotonina , Psilocibina , AnsiedadeRESUMO
Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT2A) activation, whereas LSD-induced head twitching is dependent on 5-HT2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects.
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Antidepressivos , Alucinógenos , Dietilamida do Ácido Lisérgico , Psilocibina , Receptor trkB , Alucinógenos/metabolismo , Humanos , Células HEK293 , Sítios de Ligação , Simulação de Dinâmica Molecular , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transdução de Sinais , Receptor trkB/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Antidepressivos/metabolismo , Regulação Alostérica , Masculino , Feminino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Embrião de Mamíferos/citologia , Neurônios/efeitos dos fármacos , Dietilamida do Ácido Lisérgico/química , Dietilamida do Ácido Lisérgico/metabolismo , Dietilamida do Ácido Lisérgico/farmacologia , Psilocibina/química , Psilocibina/metabolismo , Psilocibina/farmacologiaRESUMO
Brain derived neurotrophic factor (BDNF) and its receptor tropomyosin kinase receptor B (TRKB) are key regulators of activity-dependent plasticity in the brain. TRKB is the target for both slow- and rapid-acting antidepressants and BDNF-TRKB system mediates the plasticity-inducing effects of antidepressants through their downstream targets. Particularly, the protein complexes that regulate the trafficking and synapse recruitment of TRKB receptors might be crucial in this process. In the present study, we investigated the interaction of TRKB with the postsynaptic density protein 95 (PSD95). We found that antidepressants increase the TRKB:PSD95 interaction in adult mouse hippocampus. Fluoxetine, a slow-acting antidepressant, increases this interaction only after a long-term (7 days) treatment, while (2R,6R)-hydroxynorketamine (RHNK), an active metabolite of rapid-acting antidepressant ketamine, achieves this within a short treatment regimen (3 days). Moreover, the drug-induced changes of TRKB:PSD95 interaction correlate with drug latency in behaviour, observed in mice subjected to an object location memory test (OLM). While silencing of PSD95 by viral delivery of shRNA in hippocampus abolished the RHNK-induced plasticity in mice in OLM, overexpression of PSD95 shortened the fluoxetine latency. In summary, changes in the TRKB:PSD95 interaction contribute to differences observed in drug latency. This study sheds a light on a novel mechanism of action of different classes of antidepressants.
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Fator Neurotrófico Derivado do Encéfalo , Fluoxetina , Animais , Camundongos , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Fluoxetina/farmacologia , Hipocampo/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Critical period-like plasticity (iPlasticity) can be reinstated in the adult brain by several interventions, including drugs and optogenetic modifications. We have demonstrated that a combination of iPlasticity with optimal training improves behaviors related to neuropsychiatric disorders. In this context, the activation of TrkB, a receptor for BDNF, in Parvalbumin-positive (PV+) interneurons has a pivotal role in cortical network changes. However, it is unknown if the activation of TrkB in PV+ interneurons is important for other plasticity-related behaviors, especially for learning and memory. Here, using mice with heterozygous conditional TrkB deletion in PV+ interneurons (PV-TrkB hCKO) in IntelliCage and fear erasure paradigms, we show that chronic treatment with fluoxetine, a widely prescribed antidepressant drug that is known to promote the activation of TrkB, enhances behavioral flexibility in spatial and fear memory, largely depending on the expression of the TrkB receptor in PV+ interneurons. In addition, hippocampal long-term potentiation was enhanced by chronic treatment with fluoxetine in wild-type mice, but not in PV-TrkB hCKO mice. Transcriptomic analysis of PV+ interneurons after fluoxetine treatment indicated intrinsic changes in synaptic formation and downregulation of enzymes involved in perineuronal net formation. Consistently, immunohistochemistry has shown that the fluoxetine treatment alters PV expression and reduces PNNs in PV+ interneurons, and here we show that TrkB expression in PV+ interneurons is required for these effects. Together, our results provide molecular and network mechanisms for the induction of critical period-like plasticity in adulthood.
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Parvalbuminas , Reversão de Aprendizagem , Camundongos , Animais , Parvalbuminas/metabolismo , Fluoxetina/farmacologia , Receptor trkB/metabolismo , Interneurônios/fisiologia , Medo , Antidepressivos/farmacologia , Antidepressivos/metabolismoRESUMO
Ketamine has been described as a fast-acting antidepressant, exerting effects in depressed patients and in preclinical models with a rapid onset of action. The typical antidepressant fluoxetine is known to induce plasticity in the adult rodent visual cortex, as assessed by a shift in ocular dominance, a classical model of brain plasticity, and a similar effect has been described for ketamine and its metabolite 2R,6R-hydroxynorketamine (R,R-HNK). Here, we demonstrate that ketamine (at 3 or 20 mg/kg) and R,R-HNK facilitated the shift in ocular dominance in monocularly deprived mice, after three injections, throughout the 7-day monocular deprivation regimen. Notably, the comparison between the treatments indicates a higher effect size of R,R-HNK compared with ketamine. Treatment with ketamine or R,R-HNK failed to influence the levels of perineuronal nets (PNNs) surrounding parvalbumin-positive interneurons. However, we observed in vitro that both ketamine and R,R-HNK are able to disrupt the tropomyosin-related kinase B (TRKB) interaction with the protein tyrosine phosphatase sigma (PTPσ), which upon binding to PNNs dephosphorylates TRKB. These results support a model where diverse drugs promote the reinstatement of juvenile-like plasticity by directly binding TRKB and releasing it from PTPσ regulation, without necessarily reducing PNNs deposits.
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Ketamina , Animais , Camundongos , Antidepressivos/farmacologia , Depressão/metabolismo , Dominância Ocular , Interneurônios/metabolismo , Ketamina/farmacologia , Parvalbuminas , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores , TropomiosinaRESUMO
Nitric oxide (NO) has been long recognized as an important modulator of neural plasticity, but characterization of the molecular mechanisms involved - specially the guanylyl cyclase-independent ones - has been challenging. There is evidence that NO could modify BDNF-TRKB signaling, a key mediator of neuronal plasticity. However, the mechanism underlying the interplay of NO and TRKB remains unclear. Here we show that NO induces nitration of the tyrosine 816 in the TRKB receptor in vivo and in vitro, and that post-translational modification inhibits TRKB phosphorylation and binding of phospholipase Cγ1 (PLCγ1) to this same tyrosine residue. Additionally, nitration triggers clathrin-dependent endocytosis of TRKB through the adaptor protein AP-2 and ubiquitination, thereby increasing translocation of TRKB away from the neuronal surface and directing it towards lysosomal degradation. Accordingly, inhibition of nitric oxide increases TRKB phosphorylation and TRKB-dependent neurite branching in neuronal cultures. In vivo, chronic inhibition of neuronal nitric oxide synthase (nNOS) dramatically reduced TRKB nitration and facilitated TRKB signaling in the visual cortex, and promoted a shift in ocular dominance upon monocular deprivation - an indicator of increased plasticity. Altogether, our data describe and characterize a new molecular brake on plasticity, namely nitration of TRKB receptors.
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Fator Neurotrófico Derivado do Encéfalo , Óxido Nítrico , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Plasticidade Neuronal/fisiologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I , Receptor trkB/metabolismo , TirosinaRESUMO
Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB has for a long time been recognized as a critical mediator of the antidepressant drug action, but BDNF signaling has been considered to be activated indirectly through the action of typical and rapid-acting antidepressants through monoamine transporters and glutamate NMDA receptors, respectively. However, recent findings demonstrate that both typical and the fast-acting antidepressants directly bind to TrkB and thereby allosterically potentiate BDNF signaling, suggesting that TrkB is the direct target for antidepressant drugs. Increased TrkB signaling particularly in the parvalbumin-expressing interneurons orchestrates iPlasticity, a state of juvenile-like enhanced plasticity in the adult brain. iPlasticity sensitizes neuronal networks to environmental influences, enabling rewiring of networks miswired by adverse experiences. These findings have dramatically changed the position of TrkB in the antidepressant effects and they propose a new end-to-end model of the antidepressant drug action. This model emphasizes the enabling role of antidepressant treatment and the active participation of the patient in the process of recovery from mood disorders.
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Psychedelic drugs have reemerged as tools to treat several brain disorders. Cultural attitudes toward them are changing, and scientists are once again investigating the neural mechanisms through which these drugs impact brain function. The significance of this research direction is reflected by recent work, including work presented by these authors at the 2022 meeting of the Society for Neuroscience. As of 2022, there were hundreds of clinical trials recruiting participants for testing the therapeutic effects of psychedelics. Emerging evidence suggests that psychedelic drugs may exert some of their long-lasting therapeutic effects by inducing structural and functional neural plasticity. Herein, basic and clinical research attempting to elucidate the mechanisms of these compounds is showcased. Topics covered include psychedelic receptor binding sites, effects of psychedelics on gene expression, and on dendrites, and psychedelic effects on microcircuitry and brain-wide circuits. We describe unmet clinical needs and the current state of translation to the clinic for psychedelics, as well as other unanswered basic neuroscience questions addressable with future studies.
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Alucinógenos , Neurociências , Humanos , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Encéfalo , Plasticidade NeuronalRESUMO
The activation of tropomyosin receptor kinase B (TrkB), the receptor of brain-derived neurotrophic factor (BDNF), plays a key role in induced juvenile-like plasticity (iPlasticity), which allows restructuring of neural networks in adulthood. Optically activatable TrkB (optoTrkB) can temporarily and spatially evoke iPlasticity, and recently, optoTrkB (E281A) was developed as a variant that is highly sensitive to light stimulation while having lower basal activity compared to the original optoTrkB. In this study, we validate optoTrkB (E281A) activated in alpha calcium/calmodulin-dependent protein kinase type II positive (CKII+) pyramidal neurons or parvalbumin-positive (PV+) interneurons in the mouse visual cortex by immunohistochemistry. OptoTrkB (E281A) was activated in PV+ interneurons and CKII+ pyramidal neurons with blue light (488 nm) through the intact skull and fur, and through a transparent skull, respectively. LED light stimulation significantly increased the intensity of phosphorylated ERK and CREB even through intact skull and fur. These findings indicate that the highly sensitive optoTrkB (E281A) can be used in iPlasticity studies of both inhibitory and excitatory neurons, with flexible stimulation protocols in behavioural studies.
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Fator Neurotrófico Derivado do Encéfalo , Córtex Visual , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cálcio , Camundongos , Neurônios/metabolismo , Parvalbuminas/metabolismo , Receptor trkB/metabolismo , Tropomiosina/metabolismo , Córtex Visual/metabolismoRESUMO
It has been postulated that the activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr-induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress-induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed an increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre-treatment with nNOS inhibitor nω -propyl-l-arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7-NI and aminoguanidine (AMG) decreased the number of escape failures in LH and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus.
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Hipocampo , Óxido Nítrico Sintase , Animais , DNA (Citosina-5-)-Metiltransferases/genética , Inibidores Enzimáticos/farmacologia , Hipocampo/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I , RNA Mensageiro/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Estresse Fisiológico , DNA Metiltransferase 3BRESUMO
Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1-10 µM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 µM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.