scholarly journals Abnormal Rat Cortical Development Induced by Ventricular Injection of rHMGB1 Mimics the Pathophysiology of Human Cortical Dysplasia

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaolin Yang ◽  
Xiaoqing Zhang ◽  
Yuanshi Ma ◽  
Zhongke Wang ◽  
Kaixuan Huang ◽  
...  
Keyword(s):  
Excitatory Amino Acid ◽  
High Mobility ◽  
Cortical Dysplasia ◽  
Acid Decarboxylase ◽  
Cortical Lesions ◽  
Excitatory Amino Acid Transporter ◽  
Spike Wave Discharges ◽  
Layer V ◽  
Layer I ◽  
Drug Resistant Epilepsy

Cortical dysplasia (CD) is a common cause of drug-resistant epilepsy. Increasing studies have implicated innate immunity in CD with epilepsy. However, it is unclear whether innate immune factors induce epileptogenic CD. Here, we injected recombinant human high mobility group box 1 (rHMGB1) into embryonic rat ventricles to determine whether rHMGB1 can induce epileptogenic CD with pathophysiological characteristics similar to those of human CD. Compared with controls and 0.1 μg rHMGB1-treated rats, the cortical organization was severely disrupted in the 0.2 μg rHMGB1-treated rats, and microgyria and heterotopia also emerged; additionally, disoriented and deformed neurons were observed in the cortical lesions and heterotopias. Subcortical heterotopia appeared in the white matter and the gray–white junction of the 0.2 μg rHMGB1-treated rats. Moreover, there was decreased number of neurons in layer V–VI and an increased number of astrocytes in layer I and V of the cortical lesions. And the HMGB1 antagonist dexmedetomidine alleviated the changes induced by rHMGB1. Further, we found that TLR4 and NF-κB were increased after rHMGB1 administration. In addition, the excitatory receptors, N-methyl-D-aspartate receptor 1 (NR1), 2A (NR2A), and 2B (NR2B) immunoreactivity were increased, and immunoreactivity of excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2) were reduced in 0.2 μg rHMGB1-treated rats compared with controls. While there were no differences in the glutamic acid decarboxylase 65/67 (GAD65/67) immunoreactivity between the two groups. These results indicate that the excitation of cortical lesions was significantly increased. Furthermore, electroencephalogram (EEG) showed a shorter latency of seizure onset and a higher incidence of status epilepticus in the 0.2 μg rHMGB1-treated rats; the frequency and amplitude of EEG were higher in the treated rats than controls. Intriguingly, spontaneous electrographic seizure discharges were detected in the 0.2 μg rHMGB1-treated rats after 5 months of age, and spike-wave discharges of approximately 8 Hz were the most significantly increased synchronous propagated waves throughout the general brain cortex. Taken together, these findings indicate that rHMGB1 exposure during pregnancy could contribute to the development of epileptogenic CD, which mimicked some pathophysiological characteristics of human CD.

scholarly journals Abnormal Rat Cortical Development Induced by Ventricular Injection of rHMGB1 Mimicked the Pathophysiology of Human Cortical Dysplasia

2020 ◽  
Author(s):  
Xiaolin Yang ◽  
Zhang Xiaoqing ◽  
Zhongke Wang ◽  
Guolong Liu ◽  
Kaifeng Shen ◽  
...  
Keyword(s):  
Field Tests ◽  
Cortical Dysplasia ◽  
Nerve Tissue ◽  
Cortical Lesions ◽  
Sprague Dawley ◽  
Nissl Staining ◽  
Cortical Organization ◽  
Neuronal Dendrites ◽  
Spike Wave Discharges ◽  
Drug Resistant Epilepsy

Abstract Background Cortical dysplasia (CD) is a common cause of drug-resistant epilepsy. Increasingly, innate immunity is involved in CD with epilepsy. However, it is unclear whether innate immune factors contribute to induce epileptogenic CD. Here, we injected recombinant human HMGB1 (rHMGB1) into the embryonic rat ventricle to determine whether rHMGB1 can induce epileptogenic CD with pathophysiological characteristics similar to those of human CD.Methods At gestational day 14.5, rHMGB1 was injected into the ventricles of Sprague Dawley (SD) rat embryos. At 2 months postnatal, the effects of rHMGB1 on cortex construction were examined by Nissl staining; the alterations of nerve tissue were detected using immunostaining. At 3 months postnatal, the susceptibility and severity of pilocarpine-induced seizures and the spontaneous epileptic discharges were evaluated by EEG. Open-field tests, novel object recognition tests, and Morris water maze tests were performed to observe the behavior of rHMGB1-treated rats.Results The results showed cortical organization was severely disrupted in the rHMGB1-treated rats, and microgyria and heterotopia also emerged; additionally, disoriented neurons, dysmorphic neurons, and dysplastic neurons were found in the cortical lesions and heterotopias. Subcortical heterotopia also appeared in the white matter and the gray-white junction of the rHMGB1-treated rats. Moreover, the numbers of neurons and astrocytes were increased in the cortical lesions; the neuronal dendrites were thickened, randomly oriented, and frequently crossed each other. Moreover, the immunoreactivity of NR2A, NR2B, NR1, GAD65/67, EAAT1 and EAAT2 indicated that the excitation of cortical lesions and heterotopia were significantly increased. Furthermore, EEG showed more susceptibility and severity of seizures in rHMGB1-treatment rats compared with the control rats. Intriguingly, spontaneous nonepileptic seizure discharges were also detected in the rHMGB1-treated rats after 5 months of age, and spike-wave discharges of approximately 8 Hz were the most significantly increased synchronously propagated waves throughout the general brain cortex.Conclusions These results indicated that rHMGB1 exposure during pregnancy can modify the cerebral structure of offspring, which results in increased susceptibility to seizures and mimics the pathophysiological characteristics of human CD. Those results suggested that HMGB1 upregulation resulting from various insults could contribute to the development of epileptogenic CD during pregnancy.

scholarly journals Protective Effect of Memantine on Bergmann Glia and Purkinje Cells Morphology in Optogenetic Model of Neurodegeneration in Mice

2021 ◽  
Vol 22 (15) ◽  
pp. 7822
Author(s):  
Anton N. Shuvaev ◽  
Olga S. Belozor ◽  
Oleg I. Mozhei ◽  
Elena D. Khilazheva ◽  
Andrey N. Shuvaev ◽  
...  
Keyword(s):  
Excitatory Amino Acid ◽  
Average Length ◽  
Glutamate Transporter ◽  
Bergmann Glia ◽  
Spinocerebellar Ataxias ◽  
Excitatory Amino Acid Transporter ◽  
Glial Glutamate Transporter ◽  
Gfap Immunoreactivity ◽  
Cerebellar Ataxias ◽  
Receptor Blockers

Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA receptors. Therefore, NMDA receptor blockers could be considered for the management of excitotoxicity. One such drug, memantine, currently used for the treatment of Alzheimer’s disease, could potentially be used for the treatment of other forms of neurodegeneration, for example, spinocerebellar ataxias (SCA). We previously demonstrated close parallels between optogenetically induced cerebellar degeneration and SCA1. Here we induced reactive transformation of cerebellar Bergmann glia (BG) using this novel optogenetic approach and tested whether memantine could counteract changes in BG and Purkinje cell (PC) morphology and expression of the main glial glutamate transporter—excitatory amino acid transporter 1 (EAAT1). Reactive BG induced by chronic optogenetic stimulation presented increased GFAP immunoreactivity, increased thickness and decreased length of its processes. Oral memantine (~90 mg/kg/day for 4 days) prevented thickening of the processes (1.57 to 1.81 vs. 1.62 μm) and strongly antagonized light-induced reduction in their average length (186.0 to 150.8 vs. 171.9 μm). Memantine also prevented the loss of the key glial glutamate transporter EAAT1 on BG. Finally, memantine reduced the loss of PC (4.2 ± 0.2 to 3.2 ± 0.2 vs. 4.1 ± 0.3 cells per 100 μm of the PC layer). These results identify memantine as potential neuroprotective therapeutics for cerebellar ataxias.

EAAT1 is involved in transport ofl-glutamate during differentiation of the Caco-2 cell line

2000 ◽  
Vol 279 (2) ◽  
pp. G366-G373 ◽  
Author(s):  
Agnès Mordrelle ◽  
Eric Jullian ◽  
Cyrille Costa ◽  
Estelle Cormet-Boyaka ◽  
Robert Benamouzig ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Line ◽  
Excitatory Amino Acid ◽  
Kinetic Studies ◽  
Glutamate Transport ◽  
Hill Coefficient ◽  
Amino Acid Transporters ◽  
Intestinal Epithelial ◽  
Transport Capacity ◽  
Excitatory Amino Acid Transporter

Little is known concerning the expression of amino acid transporters during intestinal epithelial cell differentiation. The transport mechanism ofl-glutamate and its regulation during the differentiation process were investigated using the human intestinal Caco-2 cell line. Kinetic studies demonstrated the presence of a single, high-affinity,d-aspartate-sensitive l-glutamate transport system in both confluent and fully differentiated Caco-2 cells. This transport was clearly Na+ dependent, with a Hill coefficient of 2.9 ± 0.3, suggesting a 3 Na+-to-1 glutamate stoichiometry and corresponding to the well-characterized XA,G − system. The excitatory amino acid transporter (EAAT)1 transcript was consistently expressed in the Caco-2 cell line, whereas the epithelial and neuronal EAAT3 transporter was barely detected. In contrast with systems B0 and y+, which have previously been reported to be downregulated when Caco-2 cells stop proliferating, l-glutamate transport capacity was found to increase steadily between day 8 and day 17. This increase was correlated with the level of EAAT1 mRNA, which might reflect an increase in EAAT1 gene transcription and/or stabilization of the EAAT1 transcript.

scholarly journals MTEP, a Selective mGluR5 Antagonist, Had a Neuroprotective Effect but Did Not Prevent the Development of Spontaneous Recurrent Seizures and Behavioral Comorbidities in the Rat Lithium–Pilocarpine Model of Epilepsy

2022 ◽  
Vol 23 (1) ◽  
pp. 497
Author(s):  
Alexandra V. Dyomina ◽  
Anna A. Kovalenko ◽  
Maria V. Zakharova ◽  
Tatiana Yu. Postnikova ◽  
Alexandra V. Griflyuk ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Excitatory Amino Acid ◽  
Neuroprotective Effect ◽  
Neuronal Loss ◽  
Brain Diseases ◽  
Excitatory Amino Acid Transporter ◽  
Wide Range ◽  
Pilocarpine Model ◽  
Mglur5 Antagonist ◽  
Behavioral Impairments

Metabotropic glutamate receptors (mGluRs) are expressed predominantly on neurons and glial cells and are involved in the modulation of a wide range of signal transduction cascades. Therefore, different subtypes of mGluRs are considered a promising target for the treatment of various brain diseases. Previous studies have demonstrated the seizure-induced upregulation of mGluR5; however, its functional significance is still unclear. In the present study, we aimed to clarify the effect of treatment with the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on epileptogenesis and behavioral impairments in rats using the lithium–pilocarpine model. We found that the administration of MTEP during the latent phase of the model did not improve survival, prevent the development of epilepsy, or attenuate its manifestations in rats. However, MTEP treatment completely prevented neuronal loss and partially attenuated astrogliosis in the hippocampus. An increase in excitatory amino acid transporter 2 expression, which has been detected in treated rats, may prevent excitotoxicity and be a potential mechanism of neuroprotection. We also found that MTEP administration did not prevent the behavioral comorbidities such as depressive-like behavior, motor hyperactivity, reduction of exploratory behavior, and cognitive impairments typical in the lithium–pilocarpine model. Thus, despite the distinct neuroprotective effect, the MTEP treatment was ineffective in preventing epilepsy.

scholarly journals Light-evoked glutamate transporter EAAT5 activation coordinates with conventional feedback inhibition to control rod bipolar cell output

2020 ◽  
Vol 123 (5) ◽  
pp. 1828-1837
Author(s):  
Gregory W. Bligard ◽  
James DeBrecht ◽  
Robert G. Smith ◽  
Peter D. Lukasiewicz
Keyword(s):  
Amino Acid ◽  
Feedback Inhibition ◽  
Excitatory Amino Acid ◽  
Glutamate Transporter ◽  
Bipolar Cells ◽  
Major Contributor ◽  
Excitatory Amino Acid Transporter ◽  
Control Rod ◽  
Neuronal Output ◽  
Rod Bipolar Cells

Excitatory amino acid transporter 5 (EAAT5) glutamate transporters have a chloride channel that is strongly activated by glutamate, which modulates excitatory signaling. We found that EAAT5 is a major contributor to feedback inhibition on rod bipolar cells. Inhibition to rod bipolar cells is also mediated by GABA and glycine. GABA and glycine mediate the early phase of feedback inhibition, and EAAT5 mediates a more delayed inhibition. Together, inhibitory transmitters and EAAT5 coordinate to mediate feedback inhibition, controlling neuronal output.

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