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Functional Network of DEGs involved in epileptogenic-related processes. a Node color represents primary category, determined by order indicated in panel legend. Node size indicates degree of fold change (FC). Border color indicates direction of FC. Gray lines show functional connectivity determined by GeneMania in Cytoscape. Location in network roughly determined by category and multiple associations with neighboring and other categories. (Genes located near the center are involved in multiple categories). b Venn diagram of genes contained in network diagram in A demonstrating overlap of the genes in each category, neurogenesis (blue), receptors (red), epilepsy (gray), synaptic plasticity (yellow), and proliferation (green). Gene associations provided by IPA

Functional Network of DEGs involved in epileptogenic-related processes. a Node color represents primary category, determined by order indicated in panel legend. Node size indicates degree of fold change (FC). Border color indicates direction of FC. Gray lines show functional connectivity determined by GeneMania in Cytoscape. Location in network roughly determined by category and multiple associations with neighboring and other categories. (Genes located near the center are involved in multiple categories). b Venn diagram of genes contained in network diagram in A demonstrating overlap of the genes in each category, neurogenesis (blue), receptors (red), epilepsy (gray), synaptic plasticity (yellow), and proliferation (green). Gene associations provided by IPA

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Background: Brain-derived neurotrophic factor (BDNF) is a major signaling molecule that the brain uses to control a vast network of intracellular cascades fundamental to properties of learning and memory, and cognition. While much is known about BDNF signaling in the healthy nervous system where it controls the mitogen activated protein kinase (MA...

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... Figure S1). Genes that met these conditions were separated into the lists of the epileptogenic processes, as described above. In order to relate these genes to one another and their epileptogenic functions, we created a network that portrays their function, expression fold change, direction, and functional protein relationships in Cytoscape [42] (Fig. 5a). Using GENEMania, a Cytoscape tool containing a database of experimental data showing protein-protein interactions [43], we determined potential functional relationships. Each node in the network represents a gene while the edges represents a protein interaction. Node color is determined by the epileptogenic category. Due to the ...

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... Using a full transcriptome sequencing approach on BDNF-treated neurons with and without JAK/STAT inhibitors, Hixson et al. [126] have determined the complete pool of genes that undergo BDNF-dependent JAK/STAT-mediated regulation in cultured cortical neurons. Their analyses revealed 2869 differentially regulated genes whose expression changes after BDNF application. ...
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The purpose of this review is to summarize the current knowledge regarding the reciprocal associations between brain-derived neurotrophic factor (BDNF) and immune-inflammatory pathways and how these links may explain the involvement of this neurotrophin in the immune pathophysiology of mood disorders and schizophrenia. Toward this end, we delineated the protein–protein interaction (PPI) network centered around BDNF and searched PubMed, Scopus, Google Scholar, and Science Direct for papers dealing with the involvement of BDNF in the major psychosis, neurodevelopment, neuronal functions, and immune-inflammatory and related pathways. The PPI network was built based on the significant interactions of BDNF with neurotrophic (NTRK2, NTF4, and NGFR), immune (cytokines, STAT3, TRAF6), and cell–cell junction (CTNNB, CDH1) DEPs (differentially expressed proteins). Enrichment analysis shows that the most significant terms associated with this PPI network are the tyrosine kinase receptor (TRKR) and Src homology region two domain-containing phosphatase-2 (SHP2) pathways, tyrosine kinase receptor signaling pathways, positive regulation of kinase and transferase activity, cytokine signaling, and negative regulation of the immune response. The participation of BDNF in the immune response and its interactions with neuroprotective and cell–cell adhesion DEPs is probably a conserved regulatory process which protects against the many detrimental effects of immune activation and hyperinflammation including neurotoxicity. Lowered BDNF levels in mood disorders and schizophrenia (a) are associated with disruptions in neurotrophic signaling and activated immune-inflammatory pathways leading to neurotoxicity and (b) may interact with the reduced expression of other DEPs (CTNNB1, CDH1, or DISC1) leading to multiple aberrations in synapse and axonal functions.
... STAT3 was identified as an important factor in emotional responses, related to depression, schizophrenia, and bipolar disorder, and found to be a key coordinator of cytokine activation in cellular immune responses, and in the "immune hypothesis," it has a close link to psychopathology [21][22][23]. In addition to cytokines, the activation of STAT3 can also reflect the role of upstream regulators related to neurological function, including growth factors, hormones, and endocannabinoids [24,25]. Kwon et al. revealed that STAT3 regulates depression-related behaviors via neuronal M-CSF-mediated synaptic activity [26]. ...
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Objective: A large amount of evidence shows that the abnormal expression of miRNA plays an important role in the development of depression. Therefore, we investigated the effect of miR-124-3p on neuronal damage in the hippocampus of depression rats. Methods: The target genes of miR-124-3p were predicted by the database; the depression model was prepared by subcutaneous injection of corticosterone (CORT), and LV-miR-124-3p asponge lentiviral suspension was given to determine the weight of rats and open-field test, sugar preference experiment, Serum CORT, 5-HT, DA, and NE were measured, observe and record the behavior of rats, including behavior, diet, and hair. The expression of miR-124-3p, STAT3, Bcl-2, and Bax in rat hippocampus was measured. The rat hippocampal neuron cells were extracted and transfected with miR-124-3p inhibitor; the cells were cultured with CORT, and the cell survival rate was evaluated by MTT experiment, and the expressions of miR-124-3p, STAT3, Bcl-2, and Bax in the cells were detected. Luciferase reporter gene verifies the targeted regulation of miR-124-3p on STAT3. Results: Compared with depression rats, silencing miR-124-3p increased the weight of the rats, increased the number of open-field activities, and significantly improved the general state and pathological state of the rats. The sugar water preference rate was significantly increased, the CORT content in the serum of rats decreased significantly, and the levels of 5-HT, DA, and NE increased significantly. After the treatment of silencing miR-124-3p, the expression level of miR-124-3p was decreased, while the STAT3 mRNA and protein expression levels were increased. And the protein and mRNA expression levels of Bcl-2 were increased, and the Bax protein and mRNA expression were decreased. Cell experiments verified that silencing miR-124-3p increased cell survival, the expression level of miR-124-3p decreased remarkably, while the expression levels of STAT3 mRNA and protein increased significantly. Silencing miR-124-3p reversed the effects of CORT treatment on miR-124-3p and STAT3 in neuronal cells. The luciferase reporter gene experiment confirmed that miR-124-3p targets and regulates STAT3 expression. Conclusion: Silencing miR-124-3p may protect hippocampal neurons from damage in depression rats by upregulating STAT3 gene.
... Using a full transcriptome sequencing approach on BDNF-treated neurons with and without JAK/STAT inhibitors, Hixson et al. [125] have determined the complete pool of genes that undergo BDNF-dependent JAK/STAT-mediated regulation in cultured cortical neurons. ...
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The purpose of this review is to summarize the current knowledge regarding the reciprocal associations between BDNF and immune-inflammatory pathways and how these links may explain the involvement of this neurotrophin in the immune pathophysiology of mood disorders and schizophrenia. Toward this end, we delineated the protein-protein interaction (PPI) network centered around BDNF and searched PubMed, Scopus, Google Scholar and Science Direct for papers dealing with the involvement of BDNF in the major psychosis, neurodevelopment, neuronal functions, and immune-inflammatory and related pathways. The PPI network was built based on the significant interactions of BDNF with neurotrophic (NTRK2, NTF4, and NGFR), immune (cytokines, STAT3, TRAF6), and cell-cell junction (CTNNB, CDH1) DEPs (differentially expressed proteins). Enrichment analysis shows that the most significant terms associated with this PPI network are the tyrosine kinase receptor (TRKR) and Src homology region two domain-containing phosphatase-2 (SHP2) pathways, tyrosine kinases receptor signaling pathways, positive regulation of kinase and transferase activity, cytokine signaling, and negative regulation of the immune response. The participation of BDNF in the immune response and its interactions with neuroprotective and cell–cell adhesion DEPs is probably a conserved regulatory process which protects against the many detrimental effects of immune activation and hyperinflammation including neurotoxicity. Lowered BDNF levels in mood disorders and schizophrenia a) are associated with disruptions in neurotrophic signaling and activated immune-inflammatory pathways leading to neurotoxicity; and b) may interact with the reduced expression of other DEPs (CTNNB1, CDH1, or DISC1) leading to multiple aberrations in synapse and axonal functions.
... Atypical activation of JAK-STAT signaling is mainly related to the neuroinflammatory processes aggravating neuronal impairment in Epilepsy. Diverse stimuli of cytotoxic substances released by activated glial cells in response to prolonged seizure-induced brain damage like axon sprouting represent neuroinflammation in epilepsy [60]. The elevated levels of cytokines (TNF-α, IL-6, IL-1β) cause secondary development of seizures that are adversely associated with neuronal apoptosis by activating JAK-STAT in glial cells favoring neuroinflammation in epilepsy [32,61]. ...
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IntroductionMitochondrial dysfunction is a common denominator of neuroinflammation recognized by neuronal oxidative stress-mediated apoptosis that is well recognized by common intracellular molecular pathway-interlinked neuroinflammation and mitochondrial oxidative stress, a feature of epileptogenesis. In addition, the neuronal damage in the epileptic brain corroborated the concept of brain injury-mediated neuroinflammation, further providing an interlink between inflammation, mitochondrial dysfunction, and oxidative stress in epilepsy.Materials and methodsA systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to provide evidence of preclinical and clinically used drugs targeting such nuclear, cytosolic, and mitochondrial proteins suggesting that the correlation of mechanisms linked to neuroinflammation has been elucidated in the current review. Despite that, the evidence of elevated levels of inflammatory mediators and pro-apoptotic protein levels can provide the correlation of inflammatory responses often concerned with hyperexcitability attributing to the fact that mitochondrial redox mechanisms and higher susceptibilities to neuroinflammation result from repetitive recurring epileptic seizures. Therefore, providing an understanding of seizure-induced pathological changes read by activating neuroinflammatory cascades like NF-kB, RIPK, MAPK, ERK, JNK, and JAK-STAT signaling further related to mitochondrial damage promoting hyperexcitability.Conclusion The current review highlights the further opportunity for establishing therapeutic interventions underlying the apparent correlation of neuroinflammation mediated mitochondrial oxidative stress might contribute to common intracellular mechanisms underlying a future prospective of drug treatment targeting mitochondrial dysfunction linked to the neuroinflammation in epilepsy.
... In a similar vein, uSTAT3 mediates induction of ion channels and neurotransmitter receptors in the brain [85] and can also augment the expression of select STAT1-and STAT2-responsive genes by increasing promoter accessibility [86]. However, in several cases 'canonical' signaling can also increase the transcription of the respective STAT gene, thereby elevating uSTAT levels that leads to sustained basal transcriptional activation over a longer time frame. ...
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STAT proteins represent an important family of evolutionarily conserved transcription factors that play key roles in diverse biological processes, notably including blood and immune cell development and function. Classically, STAT proteins have been viewed as inducible activators of transcription that mediate cellular responses to extracellular signals, particularly cytokines. In this ‘canonical’ paradigm, latent STAT proteins become tyrosine phosphorylated following receptor activation, typically via downstream JAK proteins, facilitating their dimerization and translocation into the nucleus where they bind to specific sequences in the regulatory region of target genes to activate transcription. However, growing evidence has challenged this paradigm and identified alternate ‘non-canonical’ functions, such as transcriptional repression and roles outside the nucleus, with both phosphorylated and unphosphorylated STATs involved. This review provides a revised framework for understanding the diverse kaleidoscope of STAT protein functional modalities. It further discusses the implications of this framework for our understanding of STAT proteins in normal blood and immune cell biology and diseases such as cancer, and also provides an evolutionary context to place the origins of these alternative functional modalities.
... Among these pathways is the janus kinases (JAK) and signal transducer and activator of transcription (STAT), with the JAK2/STAT3 isoform being highly expressed in the cortex and hippocampus and its activation seems to be essential in recovering memory in AD and in reversal learning [19,20]. The activation of two protein familiesis involved physiologically in cell growth, survival, development and differentiation besides its association in many pathologies by affecting immune functions and cancer formation [21,22]. Nevertheless, the exact contribution of this pathway in several brain insults, as TBI and stroke is not completely comprehended, since it can trigger other pathways that can augment either neural injury or repair. ...
Article
The slightly available data about the pathogenesis process of mild repetitive traumatic brain injury (mRTBI) indicates to the necessity of further exploration of mRTBI consequences. Several cellular changes are believed to contribute to the cognitive disabilities, and neurodegenerative changes observed later in persons subjected to mRTBI. We investigated glial fibrillary acidic protein (GFAP), the important severity related biomarker, where it showed further increase after multiple trauma compared to single one. To authenticate our aim, Morin (10 mg/ kg loading dose, then twice daily 5 mg/kg for 7 days), MK-801 (1 mg/kg; i.p) and their combination were used. The results obtained has shown that all the chosen regimens opposed the upregulated dementia markers (Aβ1-40, p(Thr231)Tau) and inflammatory protein contents/expression of p(Ser53s6)NF-κBp65, TNF-α, IL-6,and IL-1β and the elevated GFAP in immune stained cortex sections. Additionally, they exerted anti-apoptotic activity by decreasing caspase-3 activity and increasing Bcl-2 contents. Saving brain tissues was evident after these thera- peutic agents via upregulating the non-canonical Wnt-1/PKC-α cue and IL-10/p(Tyr(1007/1008))JAK-2/p (Tyr705)STAT-3 signaling pathway to confirm enhancement of survival pathways on the molecular level. Such results were imitated by correcting the injury dependent deviated behavior, where Morin alone or in combi- nation enhanced behavior outcome. On one side, our study refers to the implication of two survival signaling pathways; viz.,the non-canonical Wnt-1/PKC-α and p(Tyr(1007/1008))JAK-2/p(Tyr705)STAT-3 in single and repetitive mRTBI along with distorted dementia markers, inflammation and apoptotic process that finally dis- rupted behavior. On the other side, intervention through affecting all these targets by Morin alone or with MK- 801 affords a promising neuroprotective effect.
... JAK/STAT activation due to increased levels of BDNF has been demonstrated both in vivo and in vitro in BDNF-treated primary cultured neurons as well as in the rat pilocarpine model of epilepsy (Lund et al., 2008). Studies have demonstrated that the JAK/STAT pathway activation results in the expression of the inducible cAMP early repressor (ICER) via STAT3-mediated gene regulation (Hixson et al., 2019a(Hixson et al., , 2019bLund et al., 2008;Raible et al., 2014). Further, ICER represses the gene responsible for the expression of the α1 subunit of the type (A) GABA receptor encoded by the gabra1/GABRA1 gene (Lund et al., 2008). ...
... GABRA is responsible for synthesising the GABA A receptor (the primary source of fast synaptic inhibition in the brain); the aberrant changes in GABA A receptor subunit expression linked to epileptogenesis. (Grabenstatter et al., 2014;Hixson et al., 2019aHixson et al., , 2019bLund et al., 2008;Raible et al., 2014). Apart from the activation of pro-apoptotic genes and BDNF release, other directly reported pathways contributing to epileptogenesis are the mTOR pathway and Wnt pathway. ...
Article
Despite the years of research, epilepsy remains uncontrolled in one-third of afflicted individuals and poses a health and economic burden on society. Currently available anti-epileptic drugs mainly target the excitatory-inhibitory imbalance despite targeting the underlying pathophysiology of the disease. Recent research focuses on understanding the pathophysiologic mechanisms that lead to seizure generation and on possible new treatment avenues for preventing epilepsy after a brain injury. Various signaling pathways, including the mechanistic target of rapamycin (mTOR) pathway, mitogen-activated protein kinase (MAP-ERK) pathway, JAK-STAT pathway, wnt/β-catenin signaling, cAMP pathway, and jun kinase pathway, have been suggested to play an essential role in this regard. Recent work suggests that the mTOR pathway intervenes epileptogenesis and proposes that mTOR inhibitors may have antiepileptogenic properties for epilepsy. In the same way, several animal studies have indicated the involvement of the Wnt signaling pathway in neurogenesis and neuronal death induced by seizures in different phases (acute and chronic) of seizure development. Various studies have also documented the activation of JAK-STAT signaling in epilepsy and cAMP involvement in epileptogenesis through CREB (cAMP response element-binding protein). Although studies are there, the mechanism for how components of these pathways mediate epileptogenesis requires further investigation. This review summarises the current role of various signaling pathways involved in epileptogenesis and the crosstalk among them. Furthermore, we will also discuss the mechanical base for the interaction between these pathways and how these interactions could be a new emerging promising target for future epilepsy therapies.
... The focus on STAT3 and its dependent molecular pathways originated from a set of observations which collectively propose an intricate involvement in neural function relevant to behaviour in health and disease: (i) STAT3 is a major orchestrator of cellular immune processes in response to cytokine activation, which has been highly implicated in psychopathology within the framework of the "immune hypothesis" [5][6][7][8][9][10]; (ii) besides cytokines, STAT3 activation can reflect the action of many different upstream regulators with relevance for neural function, including growth factors, hormones and endocannabinoids [11][12][13][14][15][16][17][18][19]; (iii) STAT3 importantly influences synaptic plasticity-related events [20][21][22] and can act to control gene expression through epigenetic processes [23][24][25], hereby potentially impacting on neural mechanisms relevant for psychopathology independently of its genomic activities or immune stimulation; (iv). Several indications for an interrelationship between STAT3 and the serotonergic neurotransmission system, highly implicated in the aetiology of psychiatric disorders, have also recently emerged [26,27]. ...
... Mice were kept on a 12/ 12 hour light/dark cycle in a temperature-controlled colony room (22 ± 1°C) and provided with food and water ad libitum. Single-housed male and female littermate mice (8)(9)(10)(11)(12)(13)(14)(15)(16) ...
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The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology.
... The canonical signalling pathway comprises STAT translocation into the nucleus after its phosphorylation by the ligand-activated JAK. However, there is growing evidence of non-canonical signalling in both Drosophila and mammals, whereby non-phosphorylated STAT stabilises heterochromatin by binding HP1 (Li, 2008;Hixson et al., 2019). HP1 is an evolutionarily conserved non-histone chromatin protein whose best-characterised role is the formation and propagation of heterochromatin (Lomberk et al., 2006;Dialynas et al., 2008;Xu et al., 2014). ...
Article
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Epithelial tissues rely on the adhesion between participating cells to retain their integrity. The transmembrane protein E-cadherin is the major protein that mediates homophilic adhesion between neighbouring cells and is, therefore, one of the critical components for epithelial integrity. E-cadherin downregulation has been described extensively as a prerequisite for epithelial-to-mesenchymal transition and is a hallmark in many types of cancer. Due to this clinical importance, research has been mostly focused on understanding the mechanisms leading to transcriptional repression of this adhesion molecule. However, in recent years it has become apparent that re-expression of E-cadherin is a major step in the progression of many cancers during metastasis. Here, we review the currently known molecular mechanisms of E-cadherin transcriptional activation and inhibition and highlight complex interactions between individual mechanisms. We then propose an additional mechanism, whereby the competition between adhesion complexes and heterochromatin protein-1 for binding to STAT92E fine-tunes the levels of E-cadherin expression in Drosophila but also regulates other genes promoting epithelial robustness. We base our hypothesis on both existing literature and our experimental evidence and suggest that such feedback between the cell surface and the nucleus presents a powerful paradigm for epithelial resilience.
... Both the phosphorylation and total expression of STAT3 is increased in tissue samples resected from patients with epilepsy due to hippocampal sclerosis (62), focal cortical dysplasia (62), and tumors (63). The JAK/STAT pathway is a critical cell signaling pathway in glia as well as neurons, and regulates gliogenesis (64), neuronal survival and maturation (65), and neuronal gene expression (66). The current study demonstrates that the activation of the JAK/STAT pathway that has previously been shown to occur acutely in hippocampus after epileptogenic brain insults, persists into the chronic epilepsy stage, and occurs outside of the hippocampus, in areas such as the cortex and cerebellum. ...
Article
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Epilepsy is characterized by recurrent, spontaneous seizures and is a major contributor to the global burden of neurological disease. Although epilepsy can result from a variety of brain insults, in many cases the cause is unknown and, in a significant proportion of cases, seizures cannot be controlled by available treatments. Understanding the molecular alterations that underlie or are triggered by epileptogenesis would help to identify therapeutics to prevent or control progression to epilepsy. To this end, the moderate throughput technique of Reverse Phase Protein Arrays (RPPA) was used to profile changes in protein expression in a pilocarpine mouse model of acquired epilepsy. Levels of 54 proteins, comprising phosphorylation-dependent and phosphorylation-independent components of major signaling pathways and cellular complexes, were measured in hippocampus, cortex and cerebellum of mice at six time points, spanning 15 min to 2 weeks after induction of status epilepticus. Results illustrate the time dependence of levels of the commonly studied MTOR pathway component, pS6, and show, for the first time, detailed responses during epileptogenesis of multiple components of the MTOR, MAPK, JAK/STAT and apoptosis pathways, NMDA receptors, and additional cellular complexes. Also noted are time- and brain region- specific changes in correlations among levels of functionally related proteins affecting both neurons and glia. While hippocampus and cortex are primary areas studied in pilocarpine-induced epilepsy, cerebellum also shows significant time-dependent molecular responses.