Molecular and Cellular Neuroscience最新文献

{"title":"Systemic inflammation activates coagulation and immune cell infiltration pathways in brains with propagating α-synuclein fibril aggregates","authors":"Anne-Line Strange Laursen ,&nbsp;Mikkel Vestergaard Olesen ,&nbsp;Jonas Folke ,&nbsp;Tomasz Brudek ,&nbsp;Luisa Harriet Knecht ,&nbsp;Florence Sotty ,&nbsp;Kate Lykke Lambertsen ,&nbsp;Karina Fog ,&nbsp;Louise Torp Dalgaard ,&nbsp;Susana Aznar","doi":"10.1016/j.mcn.2024.103931","DOIUrl":"10.1016/j.mcn.2024.103931","url":null,"abstract":"<div><p>Synucleinopathies are a group of diseases characterized by brain aggregates of α-synuclein (α-syn). The gradual accumulation of α-syn and the role of inflammation in early-stage pathogenesis remain poorly understood. We explored this interaction by inducing chronic inflammation in a common pre-clinical synucleinopathy mouse model. Three weeks post unilateral intra-striatal injections of human α-syn pre-formed fibrils (PFF), mice underwent repeated intraperitoneal injections of 1 mg/ml lipopolysaccharide (LPS) for 3 weeks. Histological examinations of the ipsilateral site showed phospho-α-syn regional spread and LPS-induced neutrophil recruitment to the brain vasculature. Biochemical assessment of the contralateral site confirmed spreading of α-syn aggregation to frontal cortex and a rise in intracerebral TNF-α, IL-1β, IL-10 and KC/GRO cytokines levels due to LPS. No LPS-induced exacerbation of α-syn pathology load was observed at this stage. Proteomic analysis was performed contralateral to the PFF injection site using LC-MS/MS. Subsequent downstream Reactome Gene-Set Analysis indicated that α-syn pathology alters mitochondrial metabolism and synaptic signaling. Chronic LPS-induced inflammation further lead to an overrepresentation of pathways related to fibrin clotting as well as integrin and B cell receptor signaling. Western blotting confirmed a PFF-induced increase in fibrinogen brain levels and a PFF + LPS increase in Iba1 levels, indicating activated microglia. Splenocyte profiling revealed changes in T and B cells, monocytes, and neutrophils populations due to LPS treatment in PFF injected animals. In summary, early α-syn pathology impacts energy homeostasis pathways, synaptic signaling and brain fibrinogen levels. Concurrent mild systemic inflammation may prime brain immune pathways in interaction with peripheral immunity.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"129 ","pages":"Article 103931"},"PeriodicalIF":3.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044743124000162/pdfft?md5=1838fc3f6ff8a9c348701f77d1df872d&pid=1-s2.0-S1044743124000162-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cdc42 activation is necessary for heterosynaptic cooperation and competition","authors":"Mariana Nunes ,&nbsp;Natália Madeira,&nbsp;Rosalina Fonseca","doi":"10.1016/j.mcn.2024.103921","DOIUrl":"10.1016/j.mcn.2024.103921","url":null,"abstract":"<div><p>Synapses change their weights in response to neuronal activity and in turn, neuronal networks alter their response properties and ultimately allow the brain to store information as memories. As for memories, not all events are maintained over time. Maintenance of synaptic plasticity depends on the interplay between functional changes at synapses and the synthesis of plasticity-related proteins that are involved in stabilizing the initial functional changes. Different forms of synaptic plasticity coexist in time and across the neuronal dendritic area. Thus, homosynaptic plasticity refers to activity-dependent synaptic modifications that are input-specific, whereas heterosynaptic plasticity relates to changes in non-activated synapses. Heterosynaptic forms of plasticity, such as synaptic cooperation and competition allow neurons to integrate events that occur separated by relatively large time windows, up to one hour. Here, we show that activation of Cdc42, a Rho GTPase that regulates actin cytoskeleton dynamics, is necessary for the maintenance of long-term potentiation (LTP) in a time-dependent manner. Inhibiting Cdc42 activation does not alter the time-course of LTP induction and its initial expression but blocks its late maintenance. We show that Cdc42 activation is involved in the phosphorylation of cofilin, a protein involved in modulating actin filaments and that weak and strong synaptic activation leads to similar levels on cofilin phosphorylation, despite different levels of LTP expression. We show that Cdc42 activation is required for synapses to interact by cooperation or competition, supporting the hypothesis that modulation of the actin cytoskeleton provides an activity-dependent and time-restricted permissive state of synapses allowing synaptic plasticity to occur. We found that under competition, the sequence in which synapses are activated determines the degree of LTP destabilization, demonstrating that competition is an active destabilization process. Taken together, we show that modulation of actin cytoskeleton by Cdc42 activation is necessary for the expression of homosynaptic and heterosynaptic forms of plasticity. Determining the temporal and spatial rules that determine whether synapses cooperate or compete will allow us to understand how memories are associated.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"129 ","pages":"Article 103921"},"PeriodicalIF":3.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S104474312400006X/pdfft?md5=c917b58c02eaf23ceace51cdc0fc9804&pid=1-s2.0-S104474312400006X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The exocyst subunit Sec15 is critical for proper synaptic development and function at the Drosophila NMJ","authors":"Chris J. Kang ,&nbsp;Luis E. Guzmán-Clavel ,&nbsp;Katherine Lei ,&nbsp;Martin Koo ,&nbsp;Steven To ,&nbsp;John P. Roche","doi":"10.1016/j.mcn.2023.103914","DOIUrl":"10.1016/j.mcn.2023.103914","url":null,"abstract":"<div><p>The exocyst protein complex is important for targeted vesicle fusion in a variety of cell types, however, its function in neurons is still not entirely known. We found that presynaptic knockdown (KD) of the exocyst component <em>sec15</em> by transgenic RNAi expression caused a number of unexpected morphological and physiological defects in the synapse. These include the development of active zones (AZ) devoid of essential presynaptic proteins, an increase in the branching of the presynaptic arbor, the appearance of satellite boutons, and a decrease in the amplitude of stimulated postsynaptic currents as well as a decrease in the frequency of spontaneous synaptic vesicle release. We also found the release of extracellular vesicles from the presynaptic neuron was greatly diminished in the Sec15 KDs. These effects were mimicked by presynaptic knockdown of Rab11, a protein known to interact with the exocyst. <em>sec15 RNAi</em> expression caused an increase in phosphorylated Mothers against decapentaplegic (pMad) in the presynaptic terminal, an indication of enhanced bone morphogenic protein (BMP) signaling. Some morphological phenotypes caused by Sec15 knockdown were reduced by attenuation of BMP signaling through knockdown of <em>wishful thinking (Wit</em>), while other phenotypes were unaffected. Individual knockdown of multiple proteins of the exocyst complex also displayed a morphological phenotype similar to Sec15 KD. We conclude that Sec15, functioning as part of the exocyst complex, is critically important for proper formation and function of neuronal synapses. We propose a model in which Sec15 is involved in the trafficking of vesicles from the recycling endosome to the cell membrane as well as possibly trafficking extracellular vesicles for presynaptic release and these processes are necessary for the correct structure and function of the synapse.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103914"},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044743123001082/pdfft?md5=44dcb81f68b5b0609f5ada63093ea1ac&pid=1-s2.0-S1044743123001082-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138584388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-synuclein pathology is associated with astrocyte senescence in a midbrain organoid model of familial Parkinson's disease","authors":"Mudiwa N. Muwanigwa ,&nbsp;Jennifer Modamio-Chamarro ,&nbsp;Paul M.A. Antony ,&nbsp;Gemma Gomez-Giro ,&nbsp;Rejko Krüger ,&nbsp;Silvia Bolognin ,&nbsp;Jens C. Schwamborn","doi":"10.1016/j.mcn.2024.103919","DOIUrl":"10.1016/j.mcn.2024.103919","url":null,"abstract":"<div><p>Parkinson's disease (PD) is a complex, progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain. Despite extensive research efforts, the molecular and cellular changes that precede neurodegeneration in PD are poorly understood. To address this, here we describe the use of patient specific human midbrain organoids harboring the <em>SNCA</em> triplication to investigate mechanisms underlying dopaminergic degeneration. Our midbrain organoid model recapitulates key pathological hallmarks of PD, including the aggregation of α-synuclein and the progressive loss of dopaminergic neurons. We found that these pathological hallmarks are associated with an increase in senescence associated cellular phenotypes in astrocytes including nuclear lamina defects, the presence of senescence associated heterochromatin foci, and the upregulation of cell cycle arrest genes. These results suggest a role of pathological α-synuclein in inducing astrosenescence which may, in turn, increase the vulnerability of dopaminergic neurons to degeneration.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103919"},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044743124000046/pdfft?md5=db59b16e7b32392637c0190037ff0106&pid=1-s2.0-S1044743124000046-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139670096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms","authors":"C. Beretta ,&nbsp;E. Svensson ,&nbsp;A. Dakhel ,&nbsp;M. Zyśk ,&nbsp;J. Hanrieder ,&nbsp;D. Sehlin ,&nbsp;W. Michno ,&nbsp;A. Erlandsson","doi":"10.1016/j.mcn.2024.103916","DOIUrl":"10.1016/j.mcn.2024.103916","url":null,"abstract":"<div><p>Alzheimer's disease (AD) is a neurodegenerative disorder that develops over decades. Glial cells, including astrocytes are tightly connected to the AD pathogenesis, but their impact on disease progression is still unclear. Our previous data show that astrocytes take up large amounts of aggregated amyloid-beta (Aβ) but are unable to successfully degrade the material, which is instead stored intracellularly. The aim of the present study was to analyze the astrocytic Aβ deposits composition in detail in order to understand their role in AD propagation. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ₄₂ fibrils and magnetic beads. Live cell imaging and immunocytochemistry confirmed that the ingested Aβ aggregates and beads were transported to the same lysosomal compartments in the perinuclear region, which allowed us to successfully isolate the Aβ deposits from the astrocytes. Using a battery of experimental techniques, including mass spectrometry, western blot, ELISA and electron microscopy we demonstrate that human astrocytes truncate and pack the Aβ aggregates in a way that makes them highly resistant. Moreover, the astrocytes release specifically truncated forms of Aβ via different routes and thereby expose neighboring cells to pathogenic proteins. Taken together, our study establishes a role for astrocytes in mediating Aβ pathology, which could be of relevance for identifying novel treatment targets for AD.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103916"},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044743124000010/pdfft?md5=70c6cf3b3b1c003b5b3ec4ea57e7a57c&pid=1-s2.0-S1044743124000010-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139496149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of BMP signaling restores mitral cell development impaired by FGF signaling deficits in mouse olfactory bulb","authors":"Ayako Ito,&nbsp;Claire Miller,&nbsp;Fumiaki Imamura","doi":"10.1016/j.mcn.2023.103913","DOIUrl":"10.1016/j.mcn.2023.103913","url":null,"abstract":"<div><p><span>Fibroblast growth factors (FGFs) and </span>bone morphogenic proteins<span><span><span> (BMPs) play various important roles in the development of the central nervous system<span><span>. However, the roles of FGF and BMP signaling in the development of the olfactory bulb<span> (OB) are largely unknown. In this study, we first showed the expression of FGF receptors (FGFRs) and BMP receptors (BMPRs) in OB </span></span>RGCs, radial glial cells (RGCs) in the developing OB, which generate the OB projection neurons, mitral and </span></span>tufted cells<span>. When the FGF signaling was inhibited by a dominant-negative form of FGFR1 (dnFGFR1), OB RGCs accelerated their state transition to mitral cell precursors without affecting their transcription cascade and fate. However, the mitral cell precursors could not radially migrate to form the mitral cell layer (MCL). In addition, FGF signaling inhibition reduced the expression of a BMP antagonist, </span></span>Noggin<span>, in the developing OB. When BMP signaling was suppressed by the ectopic expression of Noggin or a dominant-negative form of BMPR1a (dnBMPR1a) in the developing OB, the defect in MCL formation caused by the dnFGFR1 was rescued. However, the dnBMPR1a did not rescue the accelerated state transition of OB RGCs. These results demonstrate that FGF signaling is important for OB RGCs to maintain their self-renewal state and MCL formation. Moreover, the suppression of BMP signaling is required for mitral cells to form the MCL. This study sheds new light on the roles of FGFs and BMPs in OB development.</span></span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103913"},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A neural mass model for disturbance of alpha rhythm in the minimal hepatic encephalopathy","authors":"Jiangling Song ,&nbsp;M. Brandon Westover ,&nbsp;Rui Zhang","doi":"10.1016/j.mcn.2024.103918","DOIUrl":"10.1016/j.mcn.2024.103918","url":null,"abstract":"<div><p>One of the early markers of minimal hepatic encephalopathy (MHE) is the disruption of alpha rhythm observed in electroencephalogram (EEG) signals. However, the underlying mechanisms responsible for this occurrence remain poorly understood. To address this gap, we develop a novel biophysical model MHE-AWD-NCM, encompassing the communication dynamics between a cortical neuron population (CNP) and an astrocyte population (AP), aimed at investigating the relationship between alpha wave disturbance (AWD) and mechanistical principles, specifically concerning astrocyte-neuronal communication in the context of MHE. In addition, we introduce the concepts of peak power density and peak frequency within the alpha band as quantitative measures of AWD. Our model faithfully reproduces the characteristic EEG phenomenology during MHE and shows how impairments of communication between CNP and AP could promote AWD. The results suggest that the disruptions in feedback neurotransmission from AP to CNP, along with the inhibition of GABA uptake by AP from the extracellular space, contribute to the observed AWD. Moreover, we found that the variation of external excitatory stimuli on CNP may play a key role in AWD in MHE. Finally, the sensitivity analysis is also performed to assess the relative significance of above factors in influencing AWD. Our findings align with the physiological observations and provide a more comprehensive understanding of the complex interplay of astrocyte-neuronal communication that underlies the AWD observed in MHE, which potentially may help to explore the targeted therapeutic interventions for the early stage of hepatic encephalopathy.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103918"},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139662421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plexin-B1 and Plexin-B2 play non-redundant roles in GABAergic synapse formation","authors":"Susannah S. Adel,&nbsp;Zachary J. Pranske,&nbsp;Tess F. Kowalski,&nbsp;Nicole Kanzler,&nbsp;Roshni Ray,&nbsp;Catherine Carmona,&nbsp;Suzanne Paradis","doi":"10.1016/j.mcn.2024.103920","DOIUrl":"10.1016/j.mcn.2024.103920","url":null,"abstract":"<div><p>Synapse formation in the mammalian brain is a complex and dynamic process requiring coordinated function of dozens of molecular families such as cell adhesion molecules (CAMs) and ligand-receptor pairs (Ephs/Ephrins, Neuroligins/Neurexins, Semaphorins/Plexins). Due to the large number of molecular players and possible functional redundancies within gene families, it is challenging to determine the precise synaptogenic roles of individual molecules, which is key to understanding the consequences of mutations in these genes for brain function. Furthermore, few molecules are known to exclusively regulate either GABAergic or glutamatergic synapses, and cell and molecular mechanisms underlying GABAergic synapse formation in particular are not thoroughly understood. We previously demonstrated that Semaphorin-4D (Sema4D) regulates GABAergic synapse development in the mammalian hippocampus while having no effect on glutamatergic synapse development, and this effect occurs through binding to its high affinity receptor, Plexin-B1. In addition, we demonstrated that RNAi-mediated Plexin-B2 knock-down decreases GABAergic synapse density suggesting that both receptors function in this process. Here, we perform a structure-function study of the Plexin-B1 and Plexin-B2 receptors to identify the protein domains in each receptor which are required for its synaptogenic function. Further, we examine whether Plexin-B2 is required in the presynaptic neuron, the postsynaptic neuron, or both to regulate GABAergic synapse formation. Our data reveal that Plexin-B1 and Plexin-B2 function non-redundantly to regulate GABAergic synapse formation and suggest that the transmembrane domain may underlie functional distinctions. We also provide evidence that Plexin-B2 expression in presynaptic GABAergic interneurons, as well as postsynaptic pyramidal cells, regulates GABAergic synapse formation in hippocampus. These findings lay the groundwork for future investigations into the precise signaling pathways required for synapse formation downstream of Plexin-B receptor signaling.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103920"},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139707230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2 in Alzheimer's disease: Structure, function, therapeutic prospects, and activation challenges","authors":"Emilia Zgorzynska","doi":"10.1016/j.mcn.2024.103917","DOIUrl":"10.1016/j.mcn.2024.103917","url":null,"abstract":"<div><p><span><span>Triggering receptor expressed on myeloid cells 2<span> (TREM2) is a membrane glycoprotein<span> that plays a crucial role in the regulation of microglial survival, activation, phagocytosis, as well as in the maintenance of brain </span></span></span>homeostasis<span> and the inflammatory response to injury or neurodegeneration. This review provides a comprehensive overview of TREM2 structure and functions, highlighting the role of its variants in the development and progression of </span></span>Alzheimer's disease<span> (AD), a devastating neurodegenerative disease<span> that affects millions of people worldwide. Additionally, the article discusses the potential of TREM2 as a therapeutic target in AD, analyzing the current state of research and future prospects. Given the significant challenges associated with the activation of TREM2, particularly due to its diverse isoforms and the delicate balance required to modulate the immune response without triggering hyperactivation, this review aims to enhance our understanding of TREM2 in AD and inspire further research into this promising yet challenging therapeutic target.</span></span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103917"},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139496108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role and mechanism of EphB3 in epileptic seizures and epileptogenesis through Kalirin","authors":"Hao Huang ,&nbsp;Ling Chen ,&nbsp;Jinxian Yuan ,&nbsp;Haiqing Zhang ,&nbsp;Juan Yang ,&nbsp;Zucai Xu ,&nbsp;Yangmei Chen","doi":"10.1016/j.mcn.2023.103915","DOIUrl":"10.1016/j.mcn.2023.103915","url":null,"abstract":"<div><h3>Background</h3><p>The EphB receptor tyrosine kinase family participates in intricate signaling pathways that orchestrate neural networks, guide neuronal axon development, and modulate synaptic plasticity through interactions with surface-bound ephrinB ligands. Additionally, Kalirin, a Rho guanine nucleotide exchange factor, is notably expressed in the postsynaptic membrane of excitatory neurons and plays a role in synaptic morphogenesis. This study postulates that Kalirin may act as a downstream effector of EphB3 in epilepsy. This investigation focuses on understanding the link between EphB3 and epilepsy.</p></div><div><h3>Materials and methods</h3><p>Chronic seizure models using LiCl-pilocarpine (LiCl/Pilo) and pentylenetetrazol were developed in rats. Neuronal excitability was gauged through whole-cell patch clamp recordings on rat hippocampal slices. Real-time PCR determined Kalirin's mRNA expression, and Western blotting was employed to quantify EphB3 and Kalirin protein levels. Moreover, dendritic spine density in epileptic rats was evaluated using Golgi staining.</p></div><div><h3>Results</h3><p>Modulation of EphB3 functionality influenced acute seizure severity, latency duration, and frequency of spontaneous recurrent seizures. Golgi staining disclosed an EphB3-driven alteration in dendritic spine density within the hippocampus of epileptic rats, underscoring its pivotal role in the reconfiguration of hippocampal neural circuits. Furthermore, our data propose Kalirin as a prospective downstream mediator of the EphB3 receptor.</p></div><div><h3>Conclusions</h3><p>Our findings elucidate that EphB3 impacts the action potential dynamics in isolated rat hippocampal slices and alters dendritic spine density in the inner molecular layer of epileptic rat hippocampi, likely through Kalirin-mediated pathways. This hints at EphB3's significant role in shaping excitatory circuit loops and recurrent seizure activity via Kalirin.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103915"},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044743123001094/pdfft?md5=0901e831af72e5c05a617a22678336c1&pid=1-s2.0-S1044743123001094-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138943969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}