Regulation of NRG-1-ErbB4 signaling and neuroprotection by exogenous neuregulin-1 in a mouse model of epilepsy

Peterson, Allison R.; Garcia, Terese A.; Ford, Byron D.; Binder, Devin K.

doi:10.1016/j.nbd.2021.105545

Cited by 3 publications

(5 citation statements)

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“…Having determined that LRRC8A is dysregulated predominantly in astrocytes in the hippocampus at 7dKA, it was intriguing to discern whether any other glutamate-handling machinery was altered at this timepoint. Previously, it was determined that there is a robust downregulation of GLT-1 and EAAC1 at 7dKA ( Peterson and Binder, 2019 ; Peterson et al, 2021 ), suggesting aberrant glutamate re-uptake in the epileptic hippocampus. In an effort to assess the glutamate/GABA-glutamine cycle more comprehensively in the present study, the immunoreactivity of glutamic acid decarboxylase isoform 67 (GAD67), glutaminase (Gls1), and glutamate synthetase (GS) were evaluated at 7dKA in both the ipsilateral and contralateral dorsal hippocampus.…”

Section: Resultsmentioning

confidence: 99%

“…As for our third question, we aimed to determine whether there are concurrent changes to other glutamate-GABA/glutamine cycle components at the timepoint of maximal LRRC8A dysregulation. It was previously determined that at this early epileptogenic period, the astrocytic glutamate transporter GLT-1 is downregulated in the dentate gyrus, the astrocytic glutamate transporter GLAST exhibits no dysregulation, and the neuronal glutamate transporter EAAC1 is downregulated in the ipsilateral hippocampal CA1 domain ( Peterson and Binder, 2019 ; Peterson et al, 2021 ). These findings demonstrated significant disruption to glutamate reuptake mechanisms in the epileptic hippocampus.…”

Section: Discussionmentioning

confidence: 99%

“…Animals that developed SE were collected at various timepoints corresponding to critical periods in epileptogenesis. These included 1-day post-IHKA (1dKA), coinciding with acute SE-mediated changes; 7-days post-IHKA (7dKA), coinciding with early epileptogenic changes and the onset of spontaneous seizures in this model; 14-days post-IHKA (14dKA), coinciding with mid-epileptogenic changes; and 30-days post-IHKA (30dKA), coinciding with chronic epileptogenic changes ( Lee et al, 2012 ; Peterson and Binder, 2019 ; Peterson et al, 2021 ) ( Figure 1 ).…”

Section: Methodsmentioning

confidence: 99%

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Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy

et al. 2023

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Volume-regulated anion channels (VRACs) are a group of ubiquitously expressed outwardly-rectifying anion channels that sense increases in cell volume and act to return cells to baseline volume through an efflux of anions and organic osmolytes, including glutamate. Because cell swelling, increased extracellular glutamate levels, and reduction of the brain extracellular space (ECS) all occur during seizure generation, we set out to determine whether VRACs are dysregulated throughout mesial temporal lobe epilepsy (MTLE), the most common form of adult epilepsy. To accomplish this, we employed the IHKA experimental model of MTLE, and probed for the expression of LRRC8A, the essential pore-forming VRAC subunit, at acute, early-, mid-, and late-epileptogenic time points (1-, 7-, 14-, and 30-days post-IHKA, respectively). Western blot analysis revealed the upregulation of total dorsal hippocampal LRRC8A 14-days post-IHKA in both the ipsilateral and contralateral hippocampus. Immunohistochemical analyses showed an increased LRRC8A signal 7-days post-IHKA in both the ipsilateral and contralateral hippocampus, along with layer-specific changes 1-, 7-, and 30-days post-IHKA bilaterally. LRRC8A upregulation 1 day post-IHKA was observed primarily in astrocytes; however, some upregulation was also observed in neurons. Glutamate-GABA/glutamine cycle enzymes glutamic acid decarboxylase, glutaminase, and glutamine synthetase were also dysregulated at the 7-day timepoint post status epilepticus. The timepoint-dependent upregulation of total hippocampal LRRC8A and the possible subsequent increased efflux of glutamate in the epileptic hippocampus suggest that the dysregulation of astrocytic VRAC may play an important role in the development of epilepsy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy

et al. 2023

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Section: Dear Editormentioning

confidence: 99%

“…The study demonstrated significant results in exhibiting the neuroprotective role of exogenous NRG-1 in early epilepsy mainly via increased uptake of glutamate through EAAC1 as described above, and also through upregulation of glutamine synthetase enzyme which is responsible for glutamate clearance from extracellular space. 3 In the adult brain, NRG-1/ErbB4 signaling has been observed predominantly in interneurons. Parvalbumin cells belong to a specific class of fast-spiking interneurons that are enriched with ErbB4 receptors, and the dysfunction of these inhibitory interneurons has been linked to the epileptogenesis.…”

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confidence: 99%

Role of Exogenous Neuregulin-1 as a Therapeutic Agent in Focal Epilepsy [Letter]

Gul,

Khalid,

Gul

2024

NDT

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We read with great interest the recently published article "Effects of Anti-Seizure Medication on Neuregulin-1 Gene and Protein in Patients with First-Episode Focal Epilepsy" by Zhao et al. 1 The study helps in understanding the effect of antiseizure medication (ASM) on the serum levels of Neuregulin-1 (NRG-1) mRNA and protein.The study compared the serum levels of NRG-1 mRNA and protein among patients with diagnosed focal epilepsy who were never treated with ASM before, to that of control subjects. Results revealed that the levels of NRG-1 mRNA were higher in epileptic patients post treatment with ASM, however remained lower than in healthy controls. Moreover, the levels of NRG-1 protein were found to be higher in epileptic patients both before and after treatment as compared to controls. Spearman correlation analysis demonstrated a negative correlation between the NRG-1 mRNA levels and efficacy of ASM as higher levels were found to be associated with lower frequency of seizures. However, no correlation could be found between the NRG-1 protein levels and the effectiveness of ASM. The study thus concluded that NRG-1 may serve as a therapeutic marker for focal epilepsy, and potential therapeutic targets of ASM may be investigated further. 1 Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy. Chronically elevated glutamate levels are found in patients with refractory TLE. Neuregulin-1, through its activity via epidermal growth factor receptor (ErbB4), has been known to increase glutamate uptake in neurons by upregulating excitatory amino acid transporter 1 (EAAC1). 2 A study examined the role of exogenous NRG-1 treatment at an early phase of epileptogenesis in mice. After the induction of epileptogenesis by intrahippocampal kainic acid (IHKA) injections, mice were either treated with 25 micrograms per kilogram per day of NRG-1 or 0.1% bovine serum albumin intraperitoneal daily for 7 days, followed by euthanasia. The study demonstrated significant results in exhibiting the neuroprotective role of exogenous NRG-1 in early epilepsy mainly via increased uptake of glutamate through EAAC1 as described above, and also through upregulation of glutamine synthetase enzyme which is responsible for glutamate clearance from extracellular space. 3 In the adult brain, NRG-1/ErbB4 signaling has been observed predominantly in interneurons. Parvalbumin cells belong to a specific class of fast-spiking interneurons that are enriched with ErbB4 receptors, and the dysfunction of these inhibitory interneurons has been linked to the epileptogenesis. 4 A study conducted on mice models showed that the exogenous NRG-1 increased the excitability of Parvalbumin interneurons. This effect was mediated via inhibition of Kv1 voltage gated potassium channels that lead to the shift of action potential towards more hyperpolarized levels. The study also showed that mice with specific deletion of ErbB4 were more prone to seizures after induction and exogenous NRG-1 not only delayed the onset of seizures but also decreased their inci...

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Identification of prognostic neutrophil extracellular traps-related genes subtypes predicts prognostic and immune microenvironment for osteosarcoma patients

Yang

et al. 2023

Preprint

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Background Neutrophil extracellular traps (NETs) are known to play a crucial role in tumorigenesis. The present study sought to identify a molecular subtype and prognostic signature that is based on NETs-related genes (NRGs). NRGs may provide insight into osteosarcoma molecular mechanisms and predict prognosis. Methods We search TARGET and GEO databases to obtain expression levels of NRGs and clinical data of 89 patients with osteosarcoma. Consensus clustering analysis was used to explore the molecular subtypes. The differences (variations) in immune characteristics and biological processes across various molecular subtypes were examined using GSEA, ESTIMATE, and ssGSEA. An NRG signature was constructed using LASSO regression. Kaplan-Meier (K-M) plots, Cox regressions, and nomogram analysis were performed to determine its prognostic significance in osteosarcoma. Results Molecular subtypes associated with NETs were discovered. Cluster 2 was linked to a more favorable prognosis, greater immune cell infiltration degree and immunogenicity, and a more favorable immunotherapy response than Cluster 1. Patients in the low-risk group had better survival outcomes than patients in the high-risk group. Additionally, high risk scores were independently correlated with poor prognoses as per the Cox regression analysis. Furthermore, the nomogram, which incorporates clinical characteristics and risk scores, has the potential to improve prediction accuracy. Conclusion Patients with osteosarcoma may be divided into two subtypes of NETs. An NRG-related prognostic signature was developed for patients with osteosarcoma.

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Regulation of NRG-1-ErbB4 signaling and neuroprotection by exogenous neuregulin-1 in a mouse model of epilepsy

Cited by 3 publications

References 65 publications

Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy

Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy

Role of Exogenous Neuregulin-1 as a Therapeutic Agent in Focal Epilepsy [Letter]

Identification of prognostic neutrophil extracellular traps-related genes subtypes predicts prognostic and immune microenvironment for osteosarcoma patients

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