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Methylglyoxal modification of TrkB enhances synaptic plasticity in prefrontal cortex and promotes resilience to chronic stress

ABSTRACT: Major depressive disorder (MDD) is a severe psychiatric illness that affects about 16 percent of the global population. Despite massive efforts, unravelling the pathophysiology of MDD and developing effective treatments is still a huge challenge. Here, we report a novel therapeutic axis of methylglyoxal (MGO)/tropomyosin receptor kinase B (TrkB) for treating MDD. As an endogenous metabolite, MGO was demonstrated directly binding to the extracellular domain of TrkB, provoking its dimerization and autophosphorylation. This rapidly enhances the expression of brain-derived neurotrophic factor (BDNF) and forms a BDNF-positive feedback loop. Low-dose treatment of MGO effectively promotes the hippocampal neurogenesis and exhibits sustained antidepressant effects in chronic unpredictable mild stress rat models. In addition, the modulation on MGO concentration by overexpression or inhibition of Glyoxalase 1 (GLO1) has been demonstrated associated with depression behaviors in rats. Furthermore, we also identified a natural product luteolin and its derivative lutD as potent inhibitors of GLO1 and explored their precise binding modes. Our findings reveal a novel regulatory mechanism underlying MDD and depict principles for the rational design of new antidepressants targeting GLO1.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE119482 | GEO | 2018/09/06

REPOSITORIES: GEO

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A BDNF-TrkB autocrine loop enhances senescent cell viability [RNA-seq]

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2022-09-20 | GSE190998 | GEO

BDNF-TrkB signaling orchestrates the buildup process for local sleep

Project description:Using pharmacology and optogenetics perturbations, we showed that cortical brain-derived neurotrophic factor (BDNF) regulates the intensity of SWA via the activation of Tyrosine kinase B (TrkB) receptor and cAMP-response element-binding protein (CREB). We identified that the circuitry mediating TrkB-induced sleep SWA involves excitatory pyramidal cells of the cortex's layer 5. We found that increased neuronal firing alone in the somatosensory cortex was not sufficient to increase SWA. Using mathematical modeling of a local network in the brain, we model how BDNF’s effects on synaptic strength can increase SWA in ways not achieved through increased firing alone. Together, our findings implicate BDNF-TrkB-CREB signaling pathway in local SWA control during sleep.

2024-06-22 | PXD045652 | Pride

Twist, Snail and Zeb1 targets in the context of TrkB

Project description:RK3E cells expressing TrkB and BDNF: comparison control (sh-EGFP) and sh-Twist, sh-Snail or sh-Zeb1

2011-10-12 | E-MTAB-456 | biostudies-arrayexpress

Stat3-Bdnf-TrkB axis promotes alveolar regeneration [ATAC-seq]

Project description:Regenerating new alveolar epithelium is essential for recovery from many lung diseases. This multi-cellular regenerative process occurs when type II alveolar pneumocytes (AT2), with support from mesenchymal niche cells, proliferate to generate more AT2 cells and transdifferentiate in type I pneumocytes. To elucidate how coordinated events between AT2 cells and mesenchyme restore alveolar epithelium we used unbiased genome-wide analysis of chromatin accessibility and gene expression in both cell types following acute lung injury. We observed that chromatin acessability in AT2 cells changes signficantly following acute lung injury. Newly accessible chromatin reveals new STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways in AT2 cells. Restoration of alveolar structures following both sterile and infectious lung injuries was inhibited when STAT3 signaling was lost in AT2 cells. Single-cell transcriptome analysis of regenerating AT2 cells identified brain neurotrophic factor (Bdnf) as the sole STAT3 target gene whose chromatin becomes newly accessible in a regenerating population of AT2 cells. BDNF increased alveolar organoid size and forming efficiency in murine and human models. The receptor for BDNF, TrkB, is uniquely? expressed on mesenchymal alveolar niche cells (MANC). Exposure of BDNF to TrkB increases expression of fibroblast growth factor 7 (Fgf7), an essential regenerative cytokine, in MANCs. Blocking Bdnf signaling with a TrkB receptor antagonist abrogated murine and human alveolar organoid formation. Finally, a small molecule TrkB agonist improved functional and histological outcomes in vivo following sterile and infectious lung injuries. Collectively, these data highlight the biological and therapeutic importance of the Stat3-Bdnf-TrkB axis in orchestrating alveolar epithelial regeneration

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Stat3-Bdnf-TrkB axis promotes alveolar regeneration [scRNA-seq]

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RNA-seq of human neurons derived from mutant embryonic stem cell line lacking the BDNF receptor TrkB treated with the natural TrkC receptor agonist Neurotrophin-3

Project description:RNAseq data indicate that in the human brain, most neurons co-express the brain-derived neurotrophic factor (BDNF) receptor TrkB and the Neurotrophin-3 (NT3) receptor TrkC. Because NT3 can also activate TrkB and TrkB is expressed at higher levels compared with TrkC, it has been difficult thus far to explore TrkC-mediated signaling. To this end, neurons were generated from human embryonic stem cells lacking the BDNF receptor TrkB using CRISPR/Cas9. These neurons were found to respond to very low concentrations of NT3, lower than the concentrations of BDNF needed to activate TrkB. In order to compare the transcriptional changes following treatment with NT3 RNA-seq analysis was performed and the results compared with those previously obtained following treatment of wild-type neurons with BDNF Merkouris et al. PMID: 29987039. The results indicate that downstream of TrkC activation, most of the changes in gene expression are similar to those seen after TrkB activation. The results also show that exposure to sub-saturating concentrations of either BDNF or NT3 does not cause receptor downregulation as seen with saturating ligand concentrations and that the receptors can be re-activated.

2022-03-22 | E-MTAB-11566 | biostudies-arrayexpress

TRKB Signaling Promotes Alveolar Capillary Angiogenesis Following Perinatal Hyperoxic Damage

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2024-09-15 | GSE276575 | GEO

RNA-seq of human neurons derived from H9 embryonic stem cell lines treated with BDNF, TrkB agonist ZEB 85 or NT4 against untreated controls

Project description:As a result of a large number of in vitro as well as in vivo experiments with rodents, brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB are now widely appreciated to play major roles in brain function. There is also a growing appreciation that decreased BDNF signalling may be a significant component in a wide range of brain dysfunction in humans based on the discovery of mutations and polymorphisms in the corresponding genes. Human neurons generated in vitro had been shown to be responsive to TrkB phosphorylation upon treatment with BNDF, TrkB agonist ZEB85, the related factor neurotrophin-4 (NT4). In order to compare the transcriptional changes upon treatment with the three TrkB ligands RNA-seq analysis was deployed. Cultures had been treated in triplicates with BDNF, ZEB85 or NT4 for 30 minutes, 2 hours, 12 hours and 24 hours, while non treated controls were lysed at each time-point.

2018-07-13 | E-MTAB-6975 | biostudies-arrayexpress

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Project description:Human neuroblastoma cells (SH-SY5Y) were engineered to have stable expression of either TrkA (NTRK1) or TrkB (NTRK2) receptors. The cells were pretreated with 0.5 μM Trametinib, 2.5 μM Gefitinib, and combination of 0.25 μM Trametinib and 1.25 μM Gefitinib. Stimulation of TrkA and TrkB-expressing SH-SY5Y cells was carried out 30 minutes following inhibitor addition, using 100 ng/mL of recombinant NGF (#450-01) and BDNF (#450-02), respectively (both from Peprotech). The stimulated and unstimulated controls are included.

2022-04-13 | PXD028943 | Pride

Effects of TrkB-ICD overexpression on the morphology, activity and transcriptome of cultured primary cortical neurons

Project description:In Alzheimer’s disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, as well as synaptic transmission and plasticity. In addition to compromising canonical BDNF signalling pathways, TrkB-FL cleavage produces an intracellular fragment (TrkB-ICD), which was shown to accumulate in the nucleus and to display tyrosine kinase activity. To dissect the role of TrkB-ICD overexpression from the loss of endogenous signaling throught TrkB-FL, we used lentiviruses to overexpress the TrkB-ICD sequence in cultured primary cortical neurons and performed morphological, electrophysiological and transcriptomics studies. While TrkB-ICD overexpression did not affect cell survival, it caused a significant decrease in the number of dendritic spines, both compared to untransduced and GFP-transduced neurons. Furthermore, TrkB-ICD overexpressing neurons presented a hyperpolarized resting membrane potential and increased frequency of miniature excitatory postsynaptic currents (mEPSCs). Finally, TrkB-ICD overexpression was associated with the upregulation of genes involved in (i) neuronal survival, growth and differentiation; (ii) neuronal cytoarchitecture and spine morphology; (iii) neurodegenerative processes, including AD; and (iv) synaptic transmission and plasticity. Overall, these results show that TrkB-ICD overexpression causes dendritic spine loss, alters excitatory synaptic transmission and causes transcriptome-wide changes, namely in genes coding for proteins involved in synaptic processes.

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