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

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

PROVIDER: PRJNA489370 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7788640_1.fastq.gz	Fastqsanger.gz
	SRR7788640_2.fastq.gz	Fastqsanger.gz
	SRR7788641_1.fastq.gz	Fastqsanger.gz
	SRR7788641_2.fastq.gz	Fastqsanger.gz
	SRR7788642_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2018-09-06 | GSE119482 | GEO

Prefrontal cortical synaptoproteome profile combined with machine learning predict resilience towards chronic social isolation in rats

Project description:Chronic social isolation (CSIS), an animal model of depression, generates two stress-response phenotypes: CSIS-resilient and CSIS-susceptible. However, the molecular mechanism underlying resilience to CSIS remains unclear. We aimed to investigate the prefrontal cortical synaptoproteome profile between CSIS-resilient, CSIS-susceptible and control rats in order to identify predictive proteins for the resilience phenotype. Comparison of CSIS-resilient versus CSIS-susceptible rats revealed downregulated glycolysis intermediate Aldoc and upregulated Cltc, Cam2a, Syn and Fasn proteins involved in neuronal transmission, synaptic vesicle trafficking and fatty acid synthesis. Comparison of CSIS-resilient and control rats revealed downregulated mitochondrial proteins Atp5f1b and Cs, and upregulated Prkcg, Slc17a7, and Sv2a proteins involved in signal transduction and synaptic trafficking. These proteins make the animal groups linearly separable, and 100% validation accuracy is achieved by standard machine learning models. In addition, we identified the most significant proteins for discriminating CSIS-resilient vs. CSIS-susceptible or control rats by using Support Vector Machine with greedy forward search and Random Forest, resulting in four panels of discriminative proteins. Proteomics-data-driven machine learning algorithms can provide a platform for accessing predictive features and provide additional insight into the molecular mechanisms of synaptic neurotransmission involved in stress resilience.

2024-04-23 | PXD047159 | Pride

Transcription profiling of mouse prefrontal cortex (ctrl vs transgenic synaptic AChE)

Project description:total prefrontal cortex RNA in female FVB/N mice (control) versus transgenic female mice overexpressing the human synaptic AChE

2008-06-16 | E-GEOD-937 | biostudies-arrayexpress

prefrontal cortex (ctrl vs transgenic synaptic AChE)

Project description:total prefrontal cortex RNA in female FVB/N mice (control) versus transgenic female mice overexpressing the human synaptic AChE Keywords: other

2004-05-01 | GSE937 | GEO

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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Zfp189 Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex

Project description:Stress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.

2019-08-22 | GSE118317 | 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

Prefrontal cortex cytoplasmic proteome and machine learning-based predictors of resilience towards chronic social isolation in rats

Project description:Chronic social isolation (CSIS) generates two stress-related phenotypes, resilience and susceptibility. Although brain energy metabolism is important in regulating social behaviors, the molecular mechanisms underlying CSIS resilience remain unclear. To identify protein changes and altered biochemical pathways and processes for resilience to CSIS, prefrontal cortical cytosolic proteomic profiling was performed comparing CSIS-resilient with CSIS-susceptible and control rats. Potential predictive proteins discriminating between the CSIS-resilient and CSIS-susceptible groups were identified by support vector machine-based sequential feature selection and random forest-based feature importance scores. Predominantly decreased levels of glycolytic enzymes, G protein-coupled receptor proteins, Ras subfamily of GTPase proteins, and antioxidant proteins were found in CSIS-resilient vs. CSIS-susceptible groups. Altered levels of Gapdh and proteins involved in microtubule and cytoskeletal organization, and calcium-binding proteins were identified between the two phenotypes. These dynamic changes were accompanied by increased levels of proteins involved in GABA synthesis, the proteasome system, nitrogen metabolism, and chaperone-mediated protein folding. The overall ratio of significantly up- and down-regulated cytosolic proteins suggests adaptive cellular alterations as part of the stress-coping process specific for the CSIS-resilient phenotype.

2024-04-23 | PXD048641 | Pride

Transcriptional alterations in dorsolateral prefrontal cortex and nucleus accumbens implicate neuroinflammation and synaptic remodeling in opioid use disorder

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ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling

Project description:Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7+/- knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7-/- suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.

2024-07-19 | GSE244550 | GEO

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