HIPPOCAMPUS
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2023
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IF 3.5
Shicheng Jiang,Bei Liu,Kaiwen Lin,Lianjun Li,Rongrong Li,Shuo Tan,Xinyu Zhang,Lei Jiang,Hong Ni,Yuanyuan Wang,Haihu Ding,Jing Hu,Hao Qian,Rongjing Ge
Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.
研究领域:
神经科学
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药理学
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分子生物学
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遗传学
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DOI
PubMed
高影响因子
EBioMedicine
·
2019
·
IF 6.68
Qin Yang,Zifeng Huang,Yangfu Luo,Fangshuo Zheng,Yida Hu,Hui Liu,Shuzhen Zhu,Miaoqing He,Demei Xu,Yun Li,Min Yang,Yi Yang,Xiaobo Wei,Xiaoya Gao,Wei Wang,Junhong Ma,Yuanlin Ma,Xuefeng Wang,Qing Wang
Background NACHT and WD repeat domain-containing protein 1 (Nwd1) is a member of the innate immune protein subfamily. Nwd1 contributes to the androgen receptor signaling pathway and is involved in axonal growth. However, the mechanisms that underlie pathophysiological dysfunction in seizures remain unclear. Methods Biochemical methods were used to assess Nwd1 expression and localization in a mouse model of kainic acid (KA)-induced acute seizures and temporal lobe epilepsy (TLE) patients. Electrophysiological recordings were used to measure the role of Nwd1 in regulating synaptic transmission and neuronal hyperexcitability in a model of magnesium-free-induced seizure in vitro . Behavioral experiments were performed, and seizure-induced pathological changes were evaluated in a KA-induced seizure model in vivo . GluN2B expression was measured and its correlation with Tyr1472-GluN2B phosphorylation was analyzed in primary hippocampal neurons. Findings We demonstrated high protein levels of Nwd1 in brain tissues obtained from mice with acute seizures and TLE patients. Silencing Nwd1 in mice using an adeno-associated virus (AAV) profoundly suppressed neuronal hyperexcitability and the occurrence of acute seizures, which may have been caused by reducing GluN2B-containing NMDA receptor-dependent glutamatergic synaptic transmission. Moreover, the decreased activation of Nwd1 reduced GluN2B expression and the phosphorylation of the GluN2B subunit at Tyr1472. Interpretation Here, we report a previously unrecognized but important role of Nwd1 in seizure models in vitro and in vivo , i.e. , modulating the phosphorylation of the GluN2B subunit at Tyr1472 and regulating neuronal hyperexcitability. Meanwhile, our findings may provide a therapeutic strategy for the treatment of epilepsy or other hyperexcitability-related neurological disorders. Fund The funders have not participated in the study design, data collection, data analysis, interpretation, or writing of the report.
研究领域:
神经科学
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分子生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Neuroscience Bulletin
·
2023
·
IF 5.6
Song Changgeng,Zhao Yan,Zhang Jiajia,Dong Ziyi,Kang Xin,Pan Yuqi,Du Jinle,Gao Yiting,Zhang Haifeng,Xi Ye,Ding Hui,Kuang Fang,Wang Wenting,Luo Ceng,Zhang Zhengping,Zhao Qinpeng,Yang Jiazhou,Jiang Wen,Wu Shengxi,Gao Fang
Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson’s disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.
研究领域:
神经科学
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神经解剖学
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病理学
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神经疾病
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产品关联
DOI
PubMed
高影响因子
Biomarker Research
·
2024
·Vol. 12
·期 1
·1-19
·
IF 9.5
Liu Quanlei,Shen Chunhao,Dai Yang,Tang Ting,Hou Changkai,Yang Hongyi,Wang Yihe,Xu Jinkun,Lu Yongchang,Wang Yunming,Shan Yongzhi,Wei Penghu,Zhao Guoguang
Background Temporal lobe epilepsy (TLE) is among the most common types of epilepsy and often leads to cognitive, emotional, and psychiatric issues due to the frequent seizures. A notable pathological change related to TLE is hippocampal sclerosis (HS), which is characterized by neuronal loss, gliosis, and an increased neuron fibre density. The mechanisms underlying TLE-HS development remain unclear, but the reactive transcriptomic changes in glial cells and neurons of the hippocampus post-epileptogenesis may provide insights.Methods To induce TLE, 200 nl of kainic acid (KA) was stereotactically injected into the hippocampal CA1 region of mice, followed by a 7-day postinjection period. Single-cell RNA sequencing (ScRNA-seq), single-nucleus RNA sequencing (SnRNA-seq), and Xenium-based spatial transcriptomics analyses were employed to evaluate the changes in mRNA expression in glial cells and neurons.Results From the ScRNA-seq and SnRNA-seq data, 31,390 glial cells and 48,221 neuronal nuclei were identified. Analysis of the differentially expressed genes (DEGs) revealed significant transcriptomic alterations in the hippocampal cells of mice with TLE, affecting hundreds to thousands of mRNAs and their signalling pathways. Enrichment analysis indicated notable activation of stress and inflammatory pathways in the TLE hippocampus, while pathways related to axonal development and neural support were suppressed. Xenium analysis demonstrated the expression of all 247 genes across mouse brain sections, revealing the spatial distributions of their expression in 27 cell types. Integrated analysis of the DEGs identified via the three sequencing techniques revealed that Spp1, Trem2, and Cd68 were upregulated in all glial cell types and in the Xenium data; Penk, Sorcs3, and Plekha2 were upregulated in all neuronal cell types and in the Xenium data; and Tle4 and Sipa1l3 were downregulated in all glial cell types and in the Xenium data.Conclusion In this study, a high-resolution single-cell transcriptomic atlas of the hippocampus in mice with TLE was established, revealing potential intrinsic mechanisms driving TLE-associated inflammatory activation and altered cell interactions. These findings provide valuable insights for further exploration of HS development and epileptogenesis.
研究领域:
神经科学
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分子生物学
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转录组学
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癫痫学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2024
·
IF 4.3
Han Meiqi,Wang Yu,Jing Luyi,Yang Gucheng,Liu Yaoyao,Mo Fan,Xu Zhaojie,Luo Jinping,Jia Qianli,Zhu Yuxin,Cao Hanwen,Cai Xinxia,Liu Juntao
The striatum plays a crucial role in studying epilepsy, as it is involved in seizure generation and modulation of brain activity. To explore the complex interplay between the striatum and epilepsy, we engineered advanced microelectrode arrays (MEAs) specifically designed for precise monitoring of striatal electrophysiological activities in rats. These observations were made during and following seizure induction, particularly three and 7 days post-initial modeling. The modification of graphene oxide (GO)/poly (3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)/platinu-m nanoparticles (PtNPs) demonstrated a marked reduction in impedance (10.5 ± 1.1 kΩ), and maintained exceptional stability, with impedance levels remaining consistently low (23 kΩ) even 14 days post-implantation. As seizure intensity escalated, we observed a corresponding increase in neuronal firing rates and local field potential power, with a notable shift towards higher frequency peaks and augmented inter-channel correlation. Significantly, during the grand mal seizures, theta and alpha bands became the dominant frequencies in the local field potential. Compared to the normal group, the spike firing rates on day 3 and 7 post-modeling were significantly higher, accompanied by a decreased firing interval. Power in both delta and theta bands exhibited an increasing trend, correlating with the duration of epilepsy. These findings offer valuable insights into the dynamic processes of striatal neural activity during the initial and latent phases of temporal lobe epilepsy and contribute to our understanding of the neural mechanisms underpinning epilepsy.
研究领域:
神经科学
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电生理学
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生物医学工程
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROSCIENCE LETTERS
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2017
·
IF 2.18
Tingting Yang,Zhenzhou Lin,Ling Xie,Yao Wang,Suyue Pan
Vasogenic edema induced by blood brain barrier disruption and neuronal loss play an important role in the epileptogenic process. 4,4′- diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) is a commonly used anion channel inhibitor that has been reported to exert an anticonvulsant effect in rat hippocampus in vitro. The present study aimed to investigate whether DIDS could prevent epileptogenic process in rat lithium-pilocarpine model of temporal lobe epilepsy. The tight junction proteins and serum extravasation were examined in the piriform cortex 3 days after status epilepticus. The findings showed that status epilepticus induced vasogenic edema. Based on these findings, rats were intracerebroventricularly infused with saline and DIDS 1 week after surgery, DIDS reduced vasogenic edema and prevented neuronal loss following status epilepticus in the piriform cortex. Moreover, spontaneous recurrent seizures were recorded by continuous video monitoring. DIDS significantly reduced the frequency and duration of spontaneous recurrent seizures from day 28 to day 42 post status epilepticus. These findings demonstrated that DIDS attenuated vasogenic edema and neuronal apoptosis and might exert disease-modifying effect in animal model of temporal lobe epilepsy. These results explored a novel therapeutic strategy for treatment of epilepsy.
研究领域:
神经科学
·
药理学
·
癫痫研究
✓ 已验证
DOI
PubMed
高影响因子
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