Frontiers in Cellular Neuroscience最新文献

{"title":"Astrocyte regulation of behavioral outputs: the versatile roles of calcium.","authors":"Gillian Imrie, Isabella Farhy-Tselnicker","doi":"10.3389/fncel.2025.1606265","DOIUrl":"https://doi.org/10.3389/fncel.2025.1606265","url":null,"abstract":"<p><p>Behavior arises from coordinated brain-wide neural and glial networks, enabling organisms to perceive, interpret, and respond to stimuli. Astrocytes play an important role in shaping behavioral output, yet the underlying molecular mechanisms are not fully understood. Astrocytes respond to intrinsic and extrinsic cues with calcium (Ca²⁺) fluctuations, which are highly heterogeneous across spatio-temporal scales, contexts, and brain regions. This heterogeneity allows astrocytes to exert dynamic regulatory effects on neuronal function but has made it challenging to understand the precise mechanisms and pathways linking astrocytic Ca²⁺ to specific behavioral outcomes, and the functional relevance of these signals remains unclear. Here, we review recent literature uncovering roles for astrocytic Ca²⁺ signaling in a wide array of behaviors, including cognitive, homeostatic, and affective focusing on its physiological roles, and potential pathological implications. We specifically highlight how different types of astrocytic Ca²⁺ signals are linked to distinct behavioral outcomes and discuss limitations and unanswered questions that remain to be addressed.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1606265"},"PeriodicalIF":4.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181488","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 translational power of Alzheimer's-based organoid models in personalized medicine: an integrated biological and digital approach embodying patient clinical history.","authors":"Cristina Dolciotti, Marco Righi, Eleonora Grecu, Marcello Trucas, Cristina Maxia, Daniela Murtas, Andrea Diana","doi":"10.3389/fncel.2025.1553642","DOIUrl":"https://doi.org/10.3389/fncel.2025.1553642","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by a multifaceted interplay of genetic, environmental, and pathological factors. Traditional diagnostic and research methods, including neuropsychological assessments, imaging, and cerebrospinal fluid (CSF) biomarkers, have advanced our understanding but remain limited by late-stage detection and challenges in modeling disease progression. The emergence of three-dimensional (3D) brain organoids (BOs) offers a transformative platform for bridging these gaps. BOs derived from patient-specific induced pluripotent stem cells (iPSCs) mimic the structural and functional complexities of the human brain. This advancement offers an alternative or complementary approach for studying AD pathology, including β-amyloid and tau protein aggregation, neuroinflammation, and aging processes. By integrating biological complexity with cutting-edge technological tools such as organ-on-a-chip systems, microelectrode arrays, and artificial intelligence-driven digital twins (DTs), it is hoped that BOs will facilitate real-time modeling of AD progression and response to interventions. These models capture central nervous system biomarkers and establish correlations with peripheral markers, fostering a holistic understanding of disease mechanisms. Furthermore, BOs provide a scalable and ethically sound alternative to animal models, advancing drug discovery and personalized therapeutic strategies. The convergence of BOs and DTs potentially represents a significant shift in AD research, enhancing predictive and preventive capacities through precise <i>in vitro</i> simulations of individual disease trajectories. This approach underscores the potential for personalized medicine, reducing the reliance on invasive diagnostics while promoting early intervention. As research progresses, integrating sporadic and familial AD models within this framework promises to refine our understanding of disease heterogeneity and drive innovations in treatment and care.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1553642"},"PeriodicalIF":4.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181908","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":"Mitochondria: the hidden engines of traumatic brain injury-driven neurodegeneration.","authors":"Olusola A Olatona, Sydney P Sterben, Sahan B S Kansakar, Aviva J Symes, Volha Liaudanskaya","doi":"10.3389/fncel.2025.1570596","DOIUrl":"10.3389/fncel.2025.1570596","url":null,"abstract":"<p><p>Mitochondria play a critical role in brain energy metabolism, cellular signaling, and homeostasis, making their dysfunction a key driver of secondary injury progression in traumatic brain injury (TBI). This review explores the relationship between mitochondrial bioenergetics, metabolism, oxidative stress, and neuroinflammation in the post-TBI brain. Mitochondrial dysfunction disrupts adenosine triphosphate (ATP) production, exacerbates calcium dysregulation, and generates reactive oxygen species, triggering a cascade of neuronal damage and neurodegenerative processes. Moreover, damaged mitochondria release damage-associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA), Cytochrome C, and ATP, triggering inflammatory pathways that amplify tissue injury. We discuss the metabolic shifts that occur post-TBI, including the transition from oxidative phosphorylation to glycolysis and the consequences of metabolic inflexibility. Potential therapeutic interventions targeting mitochondrial dynamics, bioenergetic support, and inflammation modulation are explored, highlighting emerging strategies such as mitochondrial-targeted antioxidants, metabolic substrate supplementation, and pharmacological regulators of mitochondrial permeability transition pores. Understanding these mechanisms is crucial for developing novel therapeutic approaches to mitigate neurodegeneration and enhance recovery following brain trauma.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1570596"},"PeriodicalIF":4.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142022","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":"Neuroplastin 65 deficiency leads to the impairment of visual function through affecting ribbon synapse in retina of mice.","authors":"Jiu-Jiang Zeng, Ling Chen, Li-Fen Liu, Jia-Lu Wang, Jie Cheng, Ya-Ni Zheng, Lei Zhang, Xiao-Ming Zhang, Qiong-Lan Yuan","doi":"10.3389/fncel.2025.1558334","DOIUrl":"10.3389/fncel.2025.1558334","url":null,"abstract":"<p><p>Neuroplastin 65 (NP65) is a synapse-enriched glycoprotein in the central nervous system and is implicated in synaptic plasticity. In the present study, we found that NP65 knockout (NP65 KO) mice exhibit impaired visual function, including reductions in the amplitude of b-wave in scotopic flash electroretinogram (fERG), the amplitude of N1 and P1 waves in flash visual evoked potentials (fVEP), and the constriction rate in pupillary light reflexes (PLR). In wild-type (WT) mice, NP65 is specifically enriched in the synaptic ribbon (SR) of ribbon synapses labeled by Ribeye in the retina. We found that NP65 KO mice display nearly normal architecture of the retina. However, NP65 KO mice show a significant decrease in the immunoreactivity of presynaptic postsynaptic density protein 95 (PSD95), synaptophysin (SYN) and Ribeye in the outer plexiform layer (OPL). Moreover, the electron microscopy displays a decrease in synaptic ribbons and defects in postsynaptic structures in the ribbon synapses of the OPL in NP65 KO mice. In addition, we found that the apposition of presynaptic photoreceptor axonal terminals and postsynaptic bipolar cell dendrites in the OPL is misplaced in NP65 KO mice. Finally, we show that intravitreous injection of AAV-NP65 reverses the visual dysfunction, increases Ribeye expression and restores the normal arrangement in the OPL of NP65 KO mice. Together, our findings reveal that NP65 deficiency leads to visual function impairment by affecting ribbon synapses in the OPL of mice, suggesting that NP65 is critical for visual function in mammals and a potential target for degenerative retinopathy.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1558334"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12095229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127054","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":"Editorial: Physiological and pathological changes of the retina associated with ageing.","authors":"Ana I Arroba, Eleni Beli, Jose R Hombrebueno, María Llorián-Salvador","doi":"10.3389/fncel.2025.1609473","DOIUrl":"10.3389/fncel.2025.1609473","url":null,"abstract":"","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1609473"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12095190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127053","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 potential of repurposing clemastine to promote remyelination.","authors":"Reiji Yamazaki, Nobuhiko Ohno","doi":"10.3389/fncel.2025.1582902","DOIUrl":"10.3389/fncel.2025.1582902","url":null,"abstract":"<p><p>White matter in the central nervous system comprises bundled nerve fibers myelinated by oligodendrocytes. White matter injury, characterized by the loss of oligodendrocytes and myelin, is common after ischemic brain injury, inflammatory demyelinating diseases including multiple sclerosis, and traumatic damage such as spinal cord injury. Currently, no therapies have been confirmed to promote remyelination in these diseases. Over the past decade, various reports have suggested that the anti-muscarinic drug clemastine can stimulate remyelination by oligodendrocytes. Consequently, the repurposing of clemastine as a potential treatment for a variety of neurological disorders has gained significant attention. The therapeutic effects of clemastine have been demonstrated in various animal models, and its mechanisms of action in various neurological disorders are currently being investigated. In this review, we summarize reports relating to clemastine administration for white matter injury and neurological disease and discuss the therapeutic potential of remyelination promotion.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1582902"},"PeriodicalIF":4.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119457","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":"GABAergic synaptic components are largely preserved across human and mouse neuronal models.","authors":"Beatriz Rebollo, Astghik Abrahamyan, Ulrich-Wilhelm Thomale, Angela M Kaindl, Melissa A Herman, Christian Rosenmund","doi":"10.3389/fncel.2025.1588894","DOIUrl":"10.3389/fncel.2025.1588894","url":null,"abstract":"<p><p>Synaptic transmission is essential for brain function. But which characteristics of synapse function are so crucial that they are conserved between species? In general, animal models have shaped our understanding of neuronal function, although in recent years our knowledge of human neurophysiology has vastly increased. Comparative analyses between rodent and human neurons have highlighted the similarities and differences in morpho-electrical features, but the extent to which the properties of neurotransmitter release are conserved is underexplored. In this study, we compared the intrinsic properties that determine synaptic strength in cultured GABAergic neurons from mouse and human. Our findings demonstrate that, while passive neuronal properties are different across species, synaptic properties are similar, suggesting that mechanisms of synaptic transmission are conserved between mouse and human neurons. This work provides valuable insight into the extent to which animal models reflect human synaptic components at the single cell level.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1588894"},"PeriodicalIF":4.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092922","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":"Experience-dependent plasticity of multiple receptive field properties in lateral geniculate binocular neurons during the critical period.","authors":"Meng Pan, Jingjing Ye, Yijing Yan, Ailin Chen, Xinyu Li, Xin Jiang, Wei Wang, Xin Meng, Shujian Chen, Yu Gu, Xuefeng Shi","doi":"10.3389/fncel.2025.1574505","DOIUrl":"https://doi.org/10.3389/fncel.2025.1574505","url":null,"abstract":"<p><p>The visual thalamus serves as a critical hub for feature preprocessing in visual processing pathways. Emerging evidence demonstrates that experience-dependent plasticity can be revealed by monocular deprivation (MD) in the dorsolateral geniculate nucleus (dLGN) of the thalamus. However, whether and how this thalamic plasticity induces changes in multiple receptive field properties and the potential mechanisms remain unclear. Using <i>in vivo</i> electrophysiology, here we show that binocular neurons in the dLGN of 4-day MD mice starting at P28 undergo a significant ocular dominance (OD) shift during the critical period. This OD plasticity could be attributed to the potentiation of ipsilateral eye responses but not to the depression of deprived eye responses, contrasting with conventional observations in the primary visual cortex (V1). The direction and orientation selectivity of ipsilateral eye responses, but not of contralateral eye responses in these neurons, were dramatically reduced. Developmental analysis revealed pre-critical and critical period-associated changes in densities of both GABA positive neurons and GABA_A receptor α1 subunit (GABRA1) positive neurons. However, early compensatory inhibition from V1 feedback in P18 MD mice maintained network stability with no changes in OD and feature selectivity. Mechanistically, pharmacological activation of GABA_A receptors rescued the MD-induced OD shifts and feature selectivity impairments in critical period MD mice, operating independently of the V1 feedback. Furthermore, under different contrast levels and spatial frequencies, these critical period-associated changes in receptive field properties still indicate alterations in ipsilateral eye responses alone. Together, these findings provide novel insights into the developmental mechanisms of thalamic sensory processing, highlighting the thalamus as an active participant in experience-dependent visual plasticity rather than merely a passive relay station. The identified GABA-mediated plasticity mechanisms offer potential therapeutic targets for visual system disorders.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1574505"},"PeriodicalIF":4.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12066550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992104","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":"Investigation of neuromodulation of the endbulb of Held synapse in the cochlear nucleus by serotonin and norepinephrine.","authors":"Maria Groshkova, Theocharis Alvanos, Yumeng Qi, Fangfang Wang, Carolin Wichmann, Yunfeng Hua, Tobias Moser","doi":"10.3389/fncel.2025.1575158","DOIUrl":"https://doi.org/10.3389/fncel.2025.1575158","url":null,"abstract":"<p><strong>Introduction: </strong>Synapses vary greatly in synaptic strength and plasticity, even within the same circuitry or set of pre- and postsynaptic neurons. Neuromodulation is a candidate mechanism to explain some of this variability. Neuromodulators such as monoamines can differentially regulate presynaptic function and neuronal excitability. Variability is found also for the large calyceal synapses of the auditory pathway that display high synaptic vesicle (SV) release probability (P_vr) and large postsynaptic currents <i>in vitro</i> enabling reliable and temporally precise transmission of auditory information. In this study, we investigated whether the endbulb of Held synapse formed by auditory nerve fibers onto bushy cells (BCs) in the anteroventral cochlear nucleus (AVCN) of mice is modulated by norepinephrine (NE) and serotonin (5-HT).</p><p><strong>Methods: </strong>We used electron microscopy (EM) of the cochlear nucleus (CN) to investigate the presence of monoaminergic projections. Furthermore, we performed immunohistochemistry to study the localization of monoamine transporters and receptors in the AVCN. We performed patch-clamp recordings from BCs to study spontaneous and evoked synaptic transmission as well as short-term plasticity of the endbulb of Held synapse and to investigate the excitability of the BCs.</p><p><strong>Results: </strong>We found EM evidence for putative monoaminergic varicosities in both ventral and dorsal divisions of the CN. Immunostaining for vesicular 5-HT and NE transporters revealed NE-containing and 5-HT-containing varicosities in the AVCN, juxtaposed to both endbulbs and BCs. Furthermore, we detected immunofluorescence for 5-HT_1B, 5-HT₄, and 5-HT₇ receptors (R) and α_2C-adrenergic receptors (AR) in BCs. Patch-clamp recordings from BCs revealed an increase in frequency of miniature excitatory postsynaptic currents (mEPSCs) upon application of NE but not 5-HT. Evoked synaptic transmission was unaffected by the application of either NE or 5-HT. Similarly, when studying the biophysical properties of the BCs, we did not observe effects of NE or 5-HT on low-voltage-activated K⁺ ( <math> <msubsup><mrow><mtext>K</mtext></mrow> <mrow><mtext>LVA</mtext></mrow> <mrow><mo>+</mo></mrow> </msubsup> </math> ) and hyperpolarization-activated mixed cation (HCN) channels during application.</p><p><strong>Discussion: </strong>In summary, we report evidence for the presence of monoaminergic innervation in the cochlear nucleus and for subtle functional NE-neuromodulation at the endbulb of Held synapse.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1575158"},"PeriodicalIF":4.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12066487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976592","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":"Targeting autophagy in astrocytes: a potential for neurodegenerative disease intervention.","authors":"Maja Potokar, Jernej Jorgačevski","doi":"10.3389/fncel.2025.1584767","DOIUrl":"https://doi.org/10.3389/fncel.2025.1584767","url":null,"abstract":"<p><p>Autophagy contributes to cellular homeostasis by regulating the degradation and recycling of damaged organelles and misfolded proteins. In the central nervous system (CNS), impaired autophagy contributes to inflammation, disrupts cellular metabolism, and leads to the accumulation of toxic protein aggregates that accelerate the progression of neurodegenerative diseases. In addition to its role in protein and organelle turnover, autophagy facilitates the elimination of pathogenic bacteria and viruses, whose infections can also lead to neurological diseases and neuroinflammatory processes. Astrocytes, the most abundant glial cells in the CNS, play a crucial role in maintaining neuronal homeostasis by regulating neurotransmitter balance, ion exchange, and metabolic support. During neurodegeneration, they become reactive, actively participating in neuroinflammatory responses by releasing proinflammatory cytokines, activating microglia, and removing toxic aggregates. Cytokine-mediated responses and metabolic changes in astrocytes influence neuronal viability and neurotransmission. Autophagy in astrocytes plays an important role in tuning the astrocyte-dependent activity of neurons under physiological conditions and in pathological activation of astrocytes by disease, injury or pathogenic stimuli. In this review, we highlight the contribution of astrocytes to neurodegeneration from the perspective of changes in their cytoskeleton, the autophagy process in which the cytoskeleton plays a crucial role, and the metabolic support of neurons. The modulation of autophagy at different stages has the potential to serve as an additional therapeutic target in CNS diseases.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1584767"},"PeriodicalIF":4.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12066609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989020","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}