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A novel animal model of spontaneous epilepsy: Cdk5 knockout in pericyte-specific mice. 自发性癫痫的新型动物模型:在周细胞特异性小鼠中敲除 Cdk5。
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1474231
Lin Lin, Xiaofei Hu, Weijun Hong, Tengwei Pan, Zhiren Wang, En Wang, Gang Wu

Changes in neurovascular unit components and their interactions play a crucial role in epileptogenesis and the pathological process of epilepsy. Currently, there is a lack of animal models that can accurately reflect the etiological impact of cerebrovascular lesions on epilepsy. In this study, we constructed cyclin-dependent kinase 5 conditional knockout mice in Cspg4 (pericyte marker)-positive cells using the Cre-LoxP system. The results revealed that this strain of mice exhibited significant seizure behaviors and epileptiform brain waves, loss of hippocampal and amygdala neurons, astrogliosis, decreased pericyte coverage, and reduced AQP4 polar distribution. Herein, we have developed a novel mouse model of spontaneous epilepsy, providing a critical animal model for studying the involvement of neurovascular unit factors in the development and progression of epilepsy.

神经血管单元成分的变化及其相互作用在癫痫发生和病理过程中起着至关重要的作用。目前,还缺乏能准确反映脑血管病变对癫痫病因学影响的动物模型。在本研究中,我们利用 Cre-LoxP 系统构建了 Cspg4(周细胞标志物)阳性细胞中的细胞周期蛋白依赖性激酶 5 条件性基因敲除小鼠。结果表明,该品系小鼠表现出明显的癫痫发作行为和癫痫样脑电波、海马和杏仁核神经元缺失、星形胶质细胞增多、周细胞覆盖率降低和AQP4极性分布减少。在此,我们建立了一种新型的自发性癫痫小鼠模型,为研究神经血管单元因子参与癫痫的发生和发展提供了一个重要的动物模型。
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引用次数: 0
Arid3c identifies an uncharacterized subpopulation of V2 interneurons during embryonic spinal cord development. Arid3c 确定了胚胎脊髓发育过程中一个未定性的 V2 中间神经元亚群。
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1466056
Estelle Renaux, Charlotte Baudouin, Olivier Schakman, Ondine Gay, Manon Martin, Damien Marchese, Younès Achouri, René Rezsohazy, Françoise Gofflot, Frédéric Clotman

Motor activity is organized by neuronal networks composed of motor neurons and a wide variety of pre-motor interneuron populations located in the brainstem and spinal cord. Differential expression and single-cell RNA sequencing studies recently unveiled that these populations subdivide into multiple subsets. However, some interneuron subsets have not been described yet, and the mechanisms contributing to this neuronal diversification have only been partly deciphered. In this study, we aimed to identify additional markers to further describe the diversity of spinal V2 interneuron populations. Here, we compared the transcriptome of V2 interneurons with that of the other cells of the embryonic spinal cord and extracted a list of genes enriched in V2 interneurons, including Arid3c. Arid3c identifies an uncharacterized subset of V2 that partially overlaps with V2c interneurons. These two populations are characterized by the production of Onecut factors and Sox2, suggesting that they could represent a single functional V2 unit. Furthermore, we show that the overexpression or inactivation of Arid3c does not alter V2 production, but its absence results in minor defects in locomotor execution, suggesting a possible function in subtle aspects of spinal locomotor circuit formation.

运动活动是由位于脑干和脊髓的运动神经元和各种前运动中间神经元群组成的神经元网络组织的。最近进行的差异表达和单细胞 RNA 测序研究发现,这些群体细分为多个亚群。然而,一些中间神经元亚群尚未被描述,导致这种神经元多样化的机制也只被部分破解。在本研究中,我们旨在鉴定更多标记物,以进一步描述脊髓 V2 神经元群的多样性。在这里,我们比较了 V2 中间神经元与胚胎脊髓其他细胞的转录组,并提取了 V2 中间神经元中富集的基因列表,其中包括 Arid3c。Arid3c 确定了与 V2c 中间神经元部分重叠的未定性 V2 亚群。这两个群体的特征是产生Onecut因子和Sox2,这表明它们可能代表一个单一的V2功能单元。此外,我们还发现 Arid3c 的过表达或失活并不会改变 V2 的产生,但缺失 Arid3c 会导致运动执行的轻微缺陷,这表明 Arid3c 可能在脊髓运动回路形成的微妙环节中发挥作用。
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引用次数: 0
Exploring the underlying mechanisms of exercise as therapy for multiple sclerosis: insights from preclinical studies. 探索运动治疗多发性硬化症的内在机制:临床前研究的启示。
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1460262
Yunpeng Du, Shuhan Dong, Wei Zou

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system CNS characterized by demyelination, inflammation, and neurodegenerative changes, making it the most common nontraumatic disabling neurological disease in young adults. While current pharmacological treatments primarily target immunomodulation or immunosuppression, exercise is gaining increasing attention from the scientific community as an adjunctive therapy. This review explores the potential biological mechanisms of exercise in animal models of MS, focusing on its effects on neuroprotection and inflammation. The review examines how exercise inhibits pro-inflammatory microglial reactivity, stabilizes the blood-brain barrier, and enhances neurotrophic factor expression in animal studies. Future research directions are proposed by summarizing the evidence and limitations of existing animal models of MS, emphasizing the need to further validate these mechanisms in humans to better integrate exercise into the comprehensive management of MS. Additionally, investigating exercise-induced biomarkers for MS symptom reduction may provide a scientific basis for new therapeutic strategies.

多发性硬化症(MS)是一种免疫介导的中枢神经系统疾病,以脱髓鞘、炎症和神经退行性病变为特征,是青壮年中最常见的非创伤性致残神经系统疾病。虽然目前的药物治疗主要针对免疫调节或免疫抑制,但运动作为一种辅助疗法正日益受到科学界的关注。本综述探讨了运动在多发性硬化症动物模型中的潜在生物学机制,重点关注其对神经保护和炎症的影响。综述探讨了运动如何在动物实验中抑制促炎性小胶质细胞反应、稳定血脑屏障并增强神经营养因子的表达。通过总结现有多发性硬化症动物模型的证据和局限性,提出了未来的研究方向,强调需要在人体中进一步验证这些机制,以便更好地将运动纳入多发性硬化症的综合治疗中。此外,研究运动诱导的减轻多发性硬化症症状的生物标志物可为新的治疗策略提供科学依据。
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引用次数: 0
The role of ferroptosis in neurodegenerative diseases. 铁蛋白沉积症在神经退行性疾病中的作用
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-15 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1475934
Yifan Fei, Yifei Ding

Ferroptosis represents an iron- and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.

铁变性是铁和脂质过氧化(LPO)介导的一种调节性细胞死亡(RCD)形式。最近的证据有力地表明,铁变性参与了各种神经退行性疾病(NDs),尤其是阿尔茨海默病(AD)、帕金森病(PD)、亨廷顿病(HD)、多发性硬化症(MS)和肌萎缩侧索硬化症(ALS)等。在 ND 的背景下,铁中毒的治疗既是机遇也是挑战。本综述全面概述了铁变态反应的特征、诱导和抑制,强调了铁变态反应抑制剂及其发生的内在机制。此外,该综述还探讨了这些机制如何促进主要神经退行性疾病的发病和进展。此外,它还介绍了有关铁蛋白沉积在 ND 中的作用的新见解,并总结了在开发针对铁蛋白沉积的治疗方法方面的最新进展。这些见解和进展有望指导未来的策略,从而有效控制这些使人衰弱的病症。
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引用次数: 0
Manipulation of DHPS activity affects dendritic morphology and expression of synaptic proteins in primary rat cortical neurons. 操纵 DHPS 活性会影响原代大鼠皮质神经元的树突形态和突触蛋白的表达。
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1465011
Paola Cavalli, Anna Raffauf, Sergio Passarella, Martin Helmuth, Daniela C Dieterich, Peter Landgraf

Deoxyhypusine synthase (DHPS) catalyzes the initial step of hypusine incorporation into the eukaryotic initiation factor 5A (eIF5A), leading to its activation. The activated eIF5A, in turn, plays a key role in regulating the protein translation of selected mRNAs and therefore appears to be a suitable target for therapeutic intervention strategies. In the present study, we analyzed the role of DHPS-mediated hypusination in regulating neuronal homeostasis using lentivirus-based gain and loss of function experiments in primary cortical cultures from rats. This model allows us to examine the impact of DHPS function on the composition of the dendritic and synaptic compartments, which may contribute to a better understanding of cognitive function and neurodevelopment in vivo. Our findings revealed that shRNA-mediated DHPS knockdown diminishes the amount of hypusinated eIF5A (eIF5AHyp), resulting in notable alterations in neuronal dendritic architecture. Furthermore, in neurons, the synaptic composition was also affected, showing both pre- and post-synaptic changes, while the overexpression of DHPS had only a minor impact. Therefore, we hypothesize that interfering with the eIF5A hypusination caused by reduced DHPS activity impairs neuronal and synaptic homeostasis.

脱氧羽扇豆碱合成酶(DHPS)催化羽扇豆碱掺入真核启动因子 5A(eIF5A)的初始步骤,从而导致其活化。活化的 eIF5A 反过来又在调节特定 mRNA 的蛋白质翻译中发挥关键作用,因此似乎是治疗干预策略的一个合适靶点。在本研究中,我们利用慢病毒在大鼠原代皮质培养物中进行的功能增益和缺失实验,分析了 DHPS 介导的功能减退在调节神经元稳态中的作用。这种模型使我们能够研究 DHPS 功能对树突和突触区组成的影响,这可能有助于更好地理解体内的认知功能和神经发育。我们的研究结果表明,shRNA介导的DHPS基因敲除会减少低配位eIF5A(eIF5AHyp)的数量,从而导致神经元树突结构的显著改变。此外,神经元的突触组成也受到了影响,突触前和突触后都出现了变化,而 DHPS 的过表达仅产生了轻微的影响。因此,我们推测,干扰 DHPS 活性降低所导致的 eIF5A 功能减弱会损害神经元和突触的平衡。
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引用次数: 0
A novel loss-of-function KCNB1 gene variant in a twin with global developmental delay and seizures. 在一对患有全面发育迟缓和癫痫发作的双胞胎中发现了一种新型功能缺失的 KCNB1 基因变异。
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1477989
Rían W Manville, Claire L Illeck, Cesar Santos, Richard Sidlow, Geoffrey W Abbott

Human voltage-gated potassium (Kv) channels are expressed by a 40-member gene family that is essential for normal electrical activity and is closely linked to various excitability disorders. Function-altering sequence variants in the KCNB1 gene, which encodes the neuronally expressed Kv2.1 channel, are associated with neurodevelopmental disorders including developmental delay with or without epileptic activity. In this study, we describe a 40-month-old fraternal twin who presented with severe neurodevelopmental delay. Electroencephalogram recordings at 19 months of age revealed poor sleep architecture and the presence of multifocal epileptiform discharges. The individual's fraternal twin was neurotypical, and there was no family history of neurodevelopmental delay or seizures. Whole genome sequencing at 33 months of age for the proband revealed a de novo variant in KCNB1 [c.1154C > T/p.Pro385Leu], encoding a proline-to-leucine substitution at residue 385, in the extracellular region immediately preceding Kv2.1 transmembrane segment 6 (S6). Cellular electrophysiological analysis of the effects of the gene variant in heterologously expressed Kv2.1 demonstrated that homozygous Kv2.1-P385L channels were completely non-functional. Channels generated by a 50/50 expression of wild-type Kv2.1 and Kv2.1-P385L, designed to mimic the proband's heterozygous status, revealed a partially dominant-negative effect, resulting in an 81% reduction in current magnitude. The dramatic loss of function in Kv2.1 is the most likely cause of the severe developmental delay and seizure activity in the proband, further enriching our phenotypic understanding of KCNB1 developmental encephalopathies.

人类电压门控钾(Kv)通道由一个由 40 个成员组成的基因家族表达,该家族对正常的电活动至关重要,并与各种兴奋性疾病密切相关。编码神经表达的 Kv2.1 通道的 KCNB1 基因的功能改变序列变异与神经发育障碍有关,包括伴有或不伴有癫痫活动的发育迟缓。在本研究中,我们描述了一对 40 个月大的异卵双胞胎,他们患有严重的神经发育迟缓。19 个月大时的脑电图记录显示其睡眠结构不良,并出现多灶性癫痫样放电。该患者的异卵双胞胎神经发育正常,家族中没有神经发育迟缓或癫痫发作病史。该患者在33个月大时进行的全基因组测序发现,KCNB1存在一个新变异[c.1154C > T/p.Pro385Leu],编码在紧接Kv2.1跨膜区6(S6)之前的胞外区域385位脯氨酸到亮氨酸的置换。对该基因变异在异源表达的 Kv2.1 中的影响进行的细胞电生理分析表明,同基因 Kv2.1-P385L 通道完全没有功能。野生型 Kv2.1 和 Kv2.1-P385L 各表达 50/50 所产生的通道(旨在模拟原告的杂合状态)显示出部分显性负效应,导致电流幅度降低 81%。Kv2.1功能的急剧丧失很可能是导致该受试者严重发育迟缓和癫痫活动的原因,这进一步丰富了我们对KCNB1发育性脑病的表型认识。
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引用次数: 0
Quantitative, real-time imaging of spreading depolarization-associated neuronal ROS production. 扩增去极化相关神经元 ROS 生成的定量实时成像。
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-11 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1465531
Marc André Ackermann, Susanne Monika Buchholz, Katharina Dietrich, Michael Müller

Spreading depolarization (SD) causes a massive neuronal/glial depolarization, disturbs ionic homeostasis and deranges neuronal network function. The metabolic burden imposed by SD may also generate marked amounts of reactive oxygen species (ROS). Yet, proper optical tools are required to study this aspect with spatiotemporal detail. Therefore, we earlier generated transgenic redox indicator mice. They express in excitatory projection neurons the cytosolic redox-sensor roGFP, a reduction/oxidation sensitive green fluorescent protein which is ratiometric by excitation and responds reversibly to redox alterations. Using adult male roGFPc mice, we analyzed SD-related ROS production in CA1 stratum pyramidale of submerged slices. SD was induced by K+ microinjection, O2 withdrawal or mitochondrial uncoupling (FCCP). The extracellular DC potential deflection was accompanied by a spreading wavefront of roGFP oxidation, confirming marked neuronal ROS generation. Hypoxia-induced SD was preceded by a moderate oxidation, which became intensified as the DC potential deflection occurred. Upon K+-induced SD, roGFP oxidation slowly recovered within 10-15 min in some slices. Upon FCCP-or hypoxia-induced SD, recovery was limited. Withdrawing extracellular Ca2+ markedly dampened the SD-related roGFP oxidation and improved its reversibility, confirming a key-role of neuronal Ca2+ load in SD-related ROS generation. Neither mitochondrial uncoupling, nor inhibition of NADPH oxidase or xanthine oxidase abolished the SD-related roGFP oxidation. Therefore, ROS generation during SD involves mitochondria as well as non-mitochondrial sources. This first-time analysis of SD-related ROS dynamics became possible based on quantitative redox imaging in roGFP mice, an advanced approach, which will contribute to further decipher the molecular understanding of SD in brain pathophysiology.

扩散性去极化(SD)会导致神经元/神经胶质细胞大量去极化,扰乱离子平衡并破坏神经元网络功能。SD造成的代谢负担还可能产生大量活性氧(ROS)。然而,要研究这方面的时空细节,需要适当的光学工具。因此,我们早些时候产生了转基因氧化还原指示剂小鼠。它们在兴奋性投射神经元中表达细胞膜氧化还原传感器roGFP,这是一种对还原/氧化敏感的绿色荧光蛋白,可通过激发进行比率测量,并对氧化还原改变做出可逆反应。我们利用成年雄性roGFPc小鼠分析了浸没切片CA1金字塔层中与SD相关的ROS产生情况。SD是由K+微注射、缺氧或线粒体解偶联(FCCP)诱导的。细胞外直流电位偏转伴随着roGFP氧化的扩散波阵面,证实了明显的神经元ROS生成。在缺氧诱导 SD 之前,会出现中度氧化,随着直流电位发生偏转,氧化会加剧。K+ 诱导 SD 后,一些切片的 roGFP 氧化在 10-15 分钟内缓慢恢复。在 FCCP 或缺氧诱导的 SD 中,恢复是有限的。撤出细胞外 Ca2+ 能明显抑制 SD 相关的 roGFP 氧化,并改善其可逆性,这证实了神经元 Ca2+ 负荷在 SD 相关 ROS 生成中的关键作用。线粒体解偶联、抑制 NADPH 氧化酶或黄嘌呤氧化酶都不能抑制 SD 相关的 roGFP 氧化。因此,SD 过程中 ROS 的产生既涉及线粒体,也涉及非线粒体来源。这种基于roGFP小鼠定量氧化还原成像的方法首次实现了对SD相关ROS动态的分析,是一种先进的方法,将有助于进一步破译SD在脑病理生理学中的分子认识。
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引用次数: 0
ALS-like pathology diminishes swelling of spinal astrocytes in the SOD1 animal model. 在 SOD1 动物模型中,类似 ALS 的病理变化会减轻脊髓星形胶质细胞的肿胀。
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-10 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1472374
Tereza Filipi, Jana Tureckova, Ondrej Vanatko, Martina Chmelova, Monika Kubiskova, Natalia Sirotova, Stanislava Matejkova, Lydia Vargova, Miroslava Anderova

Astrocytes are crucial for the functioning of the nervous system as they maintain the ion homeostasis via volume regulation. Pathological states, such as amyotrophic lateral sclerosis (ALS), affect astrocytes and might even cause a loss of such functions. In this study, we examined astrocytic swelling/volume recovery in both the brain and spinal cord of the SOD1 animal model to determine the level of their impairment caused by the ALS-like pathology. Astrocyte volume changes were measured in acute brain or spinal cord slices during and after exposure to hyperkalemia. We then compared the results with alterations of extracellular space (ECS) diffusion parameters, morphological changes, expression of the Kir4.1 channel and the potassium concentration measured in the cerebrospinal fluid, to further disclose the link between potassium and astrocytes in the ALS-like pathology. Morphological analysis revealed astrogliosis in both the motor cortex and the ventral horns of the SOD1 spinal cord. The activated morphology of SOD1 spinal astrocytes was associated with the results from volume measurements, which showed decreased swelling of these cells during hyperkalemia. Furthermore, we observed lower shrinkage of ECS in the SOD1 spinal ventral horns. Immunohistochemical analysis then confirmed decreased expression of the Kir4.1 channel in the SOD1 spinal cord, which corresponded with the diminished volume regulation. Despite astrogliosis, cortical astrocytes in SOD1 mice did not show alterations in swelling nor changes in Kir4.1 expression, and we did not identify significant changes in ECS parameters. Moreover, the potassium level in the cerebrospinal fluid did not deviate from the physiological concentration. The results we obtained thus suggest that ALS-like pathology causes impaired potassium uptake associated with Kir4.1 downregulation in the spinal astrocytes, but based on our data from the cortex, the functional impairment seems to be independent of the morphological state.

星形胶质细胞对神经系统的运作至关重要,因为它们通过体积调节维持离子平衡。病理状态(如肌萎缩性脊髓侧索硬化症(ALS))会影响星形胶质细胞,甚至可能导致其丧失上述功能。在这项研究中,我们检测了 SOD1 动物模型大脑和脊髓中星形胶质细胞的肿胀/体积恢复情况,以确定 ALS 类病变对它们的损害程度。我们测量了急性脑或脊髓切片在暴露于高钾血症期间和之后的星形胶质细胞体积变化。然后,我们将结果与细胞外空间(ECS)扩散参数的变化、形态学变化、Kir4.1通道的表达以及脑脊液中测得的钾浓度进行了比较,以进一步揭示钾与星形胶质细胞在ALS样病理中的联系。形态学分析显示,SOD1 运动皮层和脊髓腹侧角都出现了星形胶质细胞增生。SOD1 脊髓星形胶质细胞的活化形态与体积测量结果有关,后者显示这些细胞在高钾血症期间的肿胀程度降低。此外,我们还观察到SOD1脊髓腹角的ECS收缩程度较低。免疫组化分析随后证实,SOD1脊髓中Kir4.1通道的表达减少,这与体积调节的减弱相吻合。尽管发生了星形胶质细胞增生,但 SOD1 小鼠的皮质星形胶质细胞并没有出现肿胀或 Kir4.1 表达的变化,我们也没有发现 ECS 参数的显著变化。此外,脑脊液中的钾含量也没有偏离生理浓度。因此,我们获得的结果表明,类似 ALS 的病理变化会导致脊髓星形胶质细胞中与 Kir4.1 下调相关的钾摄取受损,但根据我们从大脑皮层获得的数据,功能受损似乎与形态状态无关。
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引用次数: 0
Alzheimer's disease induced neurons bearing PSEN1 mutations exhibit reduced excitability. 携带 PSEN1 突变的阿尔茨海默病诱导神经元表现出兴奋性降低。
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-09 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1406970
Simon Maksour, Rocio K Finol-Urdaneta, Amy J Hulme, Mauricio E Castro Cabral-da-Silva, Helena Targa Dias Anastacio, Rachelle Balez, Tracey Berg, Calista Turner, Sonia Sanz Muñoz, Martin Engel, Predrag Kalajdzic, Leszek Lisowski, Kuldip Sidhu, Perminder S Sachdev, Mirella Dottori, Lezanne Ooi

Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.

阿尔茨海默病(AD)是一种影响记忆和认知的破坏性神经退行性疾病,以神经元缺失为特征,目前尚无治愈方法。PSEN1(Presenilin 1)基因突变是早发性家族性阿尔茨海默病(fAD)最常见的病因之一。虽然神经元兴奋性的变化被认为是AD进展的早期指标,但PSEN1突变与神经元兴奋性之间的联系仍有待全面阐明。本研究检测了来自PSEN1突变S290C或A246E的fAD患者的iPSC衍生神经元(iNs),以及经CRISPR校正的同源细胞系,以研究兴奋性的早期变化。电生理学分析表明,与同源对照组相比,PSEN1突变iNs的兴奋性都有所降低。与同源对照组相比,S290C 和 A246E 突变的神经元表现出不同的被动膜特性,这表明 PSEN1 突变对神经元兴奋性有不同的影响。此外,与同源 iNs 相比,两种 PSEN1 背景均表现出更高的电压门控钾(Kv)通道电流密度,而电压门控钠(Nav)通道电流密度却相当。这表明,Nav/Kv 的不平衡导致了 fAD iNs 神经元点燃功能受损。破译 AD 的这些早期细胞和分子变化对于了解疾病的发病机制至关重要。
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引用次数: 0
Deprivation of visual input alters specific subset of inhibitory neurons and affect thalamic afferent terminals in V1 of rd1 mouse. 剥夺视觉输入会改变rd1小鼠V1中特定抑制神经元亚群并影响丘脑传入终端
IF 4.2 3区 医学 Q2 NEUROSCIENCES Pub Date : 2024-10-09 eCollection Date: 2024-01-01 DOI: 10.3389/fncel.2024.1422613
Kashish Parnami, Anushka Surana, Vineet Choudhary, Anwesha Bhattacharyya

Retinitis Pigmentosa (RP) is a heterogenous group of inherited disorder, and its progression not only affects the retina but also the primary visual cortex. This manifests imbalances in the excitatory and inhibitory neurotransmission. Here, we investigated if changes in cortical functioning is linked to alterations in GABAergic population of neurons and its two important subsets, somatostatin (SST) and parvalbumin (PV) neuron in rd1 model of retinal degeneration (RD). We demonstrate marked decrease in the proportion of SST neurons in different layers of cortex whereas PV neurons were less affected. Moreover, we found reduced expression of glutamatergic thalamic afferents (VGLUT2) due to lack of visual activity. These results suggest PV neurons are likely recruited by the cortical circuitry to increase the inhibitory drive and compensate the disrupted inhibition-excitation balance. However, reduced SST expression perhaps results in weakening of stimulus selectivity. Delineating their functional role during RD will provide insights for acquisition of high-resolution vision thereby improving current state of vision restoration.

视网膜色素变性(RP)是一种异质性遗传性疾病,其发展不仅影响视网膜,还影响初级视觉皮层。这表现为兴奋性和抑制性神经传递失衡。在此,我们研究了在视网膜变性(RD)的 rd1 模型中,皮层功能的变化是否与 GABA 能神经元群及其两个重要亚群--体视蛋白(SST)和副视蛋白(PV)神经元--的改变有关。我们发现在大脑皮层的不同层中,SST 神经元的比例明显下降,而 PV 神经元受到的影响较小。此外,我们还发现由于缺乏视觉活动,丘脑谷氨酸能传入神经元(VGLUT2)的表达减少。这些结果表明,视皮层神经元很可能被大脑皮层电路招募,以增加抑制驱动力,补偿被破坏的抑制-兴奋平衡。然而,SST 表达的减少可能会导致刺激选择性的减弱。阐明它们在 RD 期间的功能作用将为获得高分辨率视觉提供启示,从而改善目前的视觉恢复状况。
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Frontiers in Cellular Neuroscience
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