TrkB interacts with ErbB4 and regulates NRG1-induced NR2B phosphorylation in cortical neurons before synaptogenesis

Pandya, Chirayu D.; Pillai, Anilkumar

doi:10.1186/preaccept-8374202491198307

Cited by 9 publications

(18 citation statements)

References 32 publications

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“…Brain tissues and primary cortical neuronal cells were lysed in ice-cold lysis buffer 30 . Protein was electrophoretically separated on a SDS PAGE gel and transferred to a nitrocellulose membrane.…”

Section: Methodsmentioning

confidence: 99%

Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice

et al. 2016

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Serotonin (5-HT) and brain derived neurotrophic factor (BDNF) are two signaling molecules that play important regulatory roles in the development and plasticity of neural circuits that are known to be altered in depression. However, the mechanism by which 5-HT regulates BDNF signaling is unknown. In the present study, we found that 5-HT treatment increases BDNF receptor, TrkB (tropomyosin related kinase B) levels in mouse primary cortical neurons via a Rac1 (RAS-related C3 botulinum toxin substrate 1)-dependent mechanism. Significant increases in the levels of transglutaminase 2 (TG2, which is implicated in transamidation of 5-HT to Rac1) are observed in the mouse prefrontal cortex (PFC) following chronic exposure to stress. We also found that TG2 levels are increased in the postmortem PFC of depressed suicide subjects relative to matched controls. Moreover, in mice, neuronal overexpression of TG2 resulted in the atrophy of neurons and reduced levels of TrkB in the PFC as well as a depressive-like phenotype. Overexpression of TG2 in mouse cortical neurons reduced TrkB levels as a result of impaired endocytosis of TrkB. TG2 inhibition by either a viral particle or pharmacological approach attenuated behavioral deficits caused by chronic unpredictable stress. Moreover, the overexpression of TrkB in the mouse PFC ameliorated the depressive-like phenotype of TG2 overexpressed mice. Taken together, these postmortem and preclinical findings identify TG2 as a critical mediator of the altered TrkB expression and depressive-like behaviors associated with chronic exposure to stress and suggest that TG2 may represent a novel therapeutic target in depression.

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Section: Methodsmentioning

confidence: 99%

Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice

et al. 2016

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“…Similar to findings in ErbB4 studies, there is inconsistent data on BDNF alterations in the hippocampus and cortex of schizophrenia patients (Angelucci et al, 2005; Autry and Monteggia, 2012). Interestingly, other studies have described an interaction between trkB and ErbB4 signaling pathways in cortical neurons, with trkB being necessary for NRG-1 phosphorylation of NRB2 prior to synaptogenesis (Pandya and Pillai, 2014). Moreover, NRG-1 is able to increase the release of BDNF (Pandya and Pillai, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, other studies have described an interaction between trkB and ErbB4 signaling pathways in cortical neurons, with trkB being necessary for NRG-1 phosphorylation of NRB2 prior to synaptogenesis (Pandya and Pillai, 2014). Moreover, NRG-1 is able to increase the release of BDNF (Pandya and Pillai, 2014). Reduction of trkB/ErbB4 interaction is also observed in the prefrontal cortex of schizophrenia patients (Pandya and Pillai, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, NRG-1 is able to increase the release of BDNF (Pandya and Pillai, 2014). Reduction of trkB/ErbB4 interaction is also observed in the prefrontal cortex of schizophrenia patients (Pandya and Pillai, 2014). In our study, most areas with alterations in BDNF/trkB expression did not also exhibit changes in NRG-1/ErbB4 and vice versa, a major exception being the PFC where BDNF was upregulated and ErbB4 was decreased at P60.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation

Hemmerle

Ahlbrand

Bronson

et al. 2015

Schizophrenia Research

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Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of pro-inflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brain-derived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia. On gestational day 14, pregnant rats were injected with Poly I:C or vehicle. Utilizing in situ hybridization, expression of NRG-1, ErbB4, BDNF, and trkB was examined in male rat offspring at postnatal day (P) 14, P30 and P60. ErbB4 mRNA expression was significantly increased at P30 in the anterior cingulate (AC Ctx), frontal, and parietal cortices, with increases in AC Ctx expression continuing through P60. ErbB4 expression was also elevated in the prefrontal cortex (PFC) at P14. In contrast, NRG-1 mRNA was decreased in the PFC at P60. Expression of BDNF mRNA was significantly upregulated in the PFC at P60 and decreased in the AC Ctx at P14. Expression of trkB was increased in two regions, the piriform cortex at P14 and the striatum at P60. These findings demonstrate developmentally and regionally selective alterations in the expression of schizophrenia-related genes as a consequence of MIA. Further study is needed to determine contributions of these effects to development of alterations of relevance to neuropsychiatric diseases.

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“…These inhibitors did not produce inhibition of neurite outgrowth in PC12 cells (unpublished data). We note that a few other studies also used higher concentrations of these inhibitors (Yang and Wang, 2009;Pandya and Pillai, 2014). It is possible that differences in the purity or sources of inhibitors account for the apparent discrepancy in the concentrations at which these inhibitors are effective.…”

Section: Discussionmentioning

confidence: 99%

Neuritogenic Activity of Tetradecyl 2,3-Dihydroxybenzoate Is Mediated through the Insulin-Like Growth Factor 1 Receptor/Phosphatidylinositol 3 Kinase/Mitogen-Activated Protein Kinase Signaling Pathway

Tang¹,

Gao²,

Kawatani³

et al. 2015

Mol Pharmacol

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Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from neuritogenic gentisides. In the present study, we investigated the mechanism by which ABG-001 induces neurite outgrowth in a rat adrenal pheochromocytoma cell line (PC12). Inhibitors of insulin-like growth factor 1 (IGF-1) receptor, phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinase (ERK) 1/2 significantly decreased ABG-001-induced neurite outgrowth. Western blot analysis revealed that ABG-001 significantly induced phosphorylation of IGF-1 receptor, protein kinase B (Akt), ERK, and cAMP responsive element-binding protein (CREB). These effects were markedly reduced by addition of the corresponding inhibitors. We also found that ABG-001-induced neurite outgrowth was reduced by protein kinase C inhibitor as well as small-interfering RNA against the IGF-1 receptor. Furthermore, like ABG-001, IGF-1 also induced neurite outgrowth of PC12 cells, and low-dose nerve growth factor augmented the observed effects of ABG-001 on neurite outgrowth. These results suggest that ABG-001 targets the IGF-1 receptor and activates PI3K, mitogen-activated protein kinase, and their downstream signaling cascades to induce neurite outgrowth.

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TrkB interacts with ErbB4 and regulates NRG1-induced NR2B phosphorylation in cortical neurons before synaptogenesis

Cited by 9 publications

References 32 publications

Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice

Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice

Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation

Neuritogenic Activity of Tetradecyl 2,3-Dihydroxybenzoate Is Mediated through the Insulin-Like Growth Factor 1 Receptor/Phosphatidylinositol 3 Kinase/Mitogen-Activated Protein Kinase Signaling Pathway

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