Frontiers in Molecular Neuroscience最新文献

{"title":"Fluorescence lifetime imaging of AMPA receptor endocytosis in living neurons: effects of Aβ and PP1","authors":"Katie Prinkey, Emily Thompson, Junmi M. Saikia, Tania Cid, Kim Dore","doi":"10.3389/fnmol.2024.1409401","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1409401","url":null,"abstract":"The relative amount of AMPA receptors expressed at the surface of neurons can be measured using superecliptic pHluorin (SEP) labeling at their N-terminus. However, the high signal variability resulting from protein overexpression in neurons and the low signal observed in intracellular vesicles make quantitative characterization of receptor trafficking difficult. Here, we establish a real-time live-cell assay of AMPAR trafficking based on fluorescence lifetime imaging (FLIM), which allows for simultaneous visualization of both surface and intracellular receptors. Using this assay, we found that elevating amyloid-beta (Aβ) levels leads to a strong increase in intracellular GluA1 and GluA2-containing receptors, indicating that Aβ triggers the endocytosis of these AMPARs. In APP/PS1 Alzheimer's disease model mouse neurons, FLIM revealed strikingly different AMPAR trafficking properties for GluA1- and GluA3-containing receptors, suggesting that chronic Aβ exposure triggered the loss of both surface and intracellular GluA3-containing receptors. Interestingly, overexpression of protein phosphatase 1 (PP1) also resulted in GluA1 endocytosis as well as depressed synaptic transmission, confirming the important role of phosphorylation in regulating AMPAR trafficking. This new approach allows for the quantitative measurement of extracellular pH, small changes in receptor trafficking, as well as simultaneous measurement of surface and internalized AMPARs in living neurons, and could therefore be applied to several different studies in the future.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":" 761","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141364129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can repetitive mechanical motion cause structural damage to axons?","authors":"Allegra Coppini, Alessandro Falconieri, Oz Mualem, Syeda Rubaiya Nasrin, Marine Roudon, Gadiel Saper, Henry Hess, Akira Kakugo, V. Raffa, Orit Shefi","doi":"10.3389/fnmol.2024.1371738","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1371738","url":null,"abstract":"Biological structures have evolved to very efficiently generate, transmit, and withstand mechanical forces. These biological examples have inspired mechanical engineers for centuries and led to the development of critical insights and concepts. However, progress in mechanical engineering also raises new questions about biological structures. The past decades have seen the increasing study of failure of engineered structures due to repetitive loading, and its origin in processes such as materials fatigue. Repetitive loading is also experienced by some neurons, for example in the peripheral nervous system. This perspective, after briefly introducing the engineering concept of mechanical fatigue, aims to discuss the potential effects based on our knowledge of cellular responses to mechanical stresses. A particular focus of our discussion are the effects of mechanical stress on axons and their cytoskeletal structures. Furthermore, we highlight the difficulty of imaging these structures and the promise of new microscopy techniques. The identification of repair mechanisms and paradigms underlying long-term stability is an exciting and emerging topic in biology as well as a potential source of inspiration for engineers.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":" 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141371440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise-induced neuroplasticity: a new perspective on rehabilitation for chronic low back pain","authors":"Jianpeng Zou, Shijie Hao","doi":"10.3389/fnmol.2024.1407445","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1407445","url":null,"abstract":"Chronic low back pain patients often experience recurrent episodes due to various peripheral and central factors, leading to physical and mental impairments, affecting their daily life and work, and increasing the healthcare burden. With the continuous advancement of neuropathological research, changes in brain structure and function in chronic low back pain patients have been revealed. Neuroplasticity is an important mechanism of self-regulation in the brain and plays a key role in neural injury repair. Targeting neuroplasticity and regulating the central nervous system to improve functional impairments has become a research focus in rehabilitation medicine. Recent studies have shown that exercise can have beneficial effects on the body, such as improving cognition, combating depression, and enhancing athletic performance. Exercise-induced neuroplasticity may be a potential mechanism through which exercise affects the brain. This article systematically introduces the theory of exercise-induced neuroplasticity, explores the central effects mechanism of exercise on patients with chronic low back pain, and further looks forward to new directions in targeted neuroplasticity-based rehabilitation treatment for chronic low back pain.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":" 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141372176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ahnak in the prefrontal cortex mediates behavioral correlates of stress resilience and rapid antidepressant action in mice","authors":"Dionnet L. Bhatti, Junghee Jin, Jia Cheng, Kathryn A. McCabe, Ko-Woon Lee, Clara Berdasco, Yu Young Jeong, Subhash C. Sinha, Yong Kim","doi":"10.3389/fnmol.2024.1350716","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1350716","url":null,"abstract":"The prefrontal cortex (PFC) is a key neural node mediating behavioral responses to stress and the actions of ketamine, a fast-acting antidepressant. The molecular mechanisms underlying these processes, however, are not fully understood. Our recent study revealed a pivotal role of hippocampal Ahnak as a regulator of cellular and behavioral adaptations to chronic stress. However, despite its significant expression in the PFC, the contribution of cortical Ahnak to behavioral responses to stress and antidepressants remains unknown. Here, using a mouse model for chronic social stress, we find that Ahnak expression in the PFC is significantly increased in stress-resilient mice and positively correlated with social interaction after stress exposure. Conditional deletion of Ahnak in the PFC or forebrain glutamatergic neurons facilitates stress susceptibility, suggesting that Ahnak is required for behavioral resilience. Further supporting this notion, Ahnak expression in the PFC is increased after the administration of ketamine or its metabolite (2R, 6R)-hydroxynorketamine (HNK). Moreover, Ahnak deletion in forebrain glutamatergic neurons blocks the restorative behavioral effects of ketamine or HNK in stress-susceptible mice. This forebrain excitatory neuron-specific Ahnak deletion reduces the frequency of mini excitatory postsynaptic currents in layer II/III pyramidal neurons, suggesting that Ahnak may induce its behavioral effects via modulation of glutamatergic transmission in the PFC. Altogether, these data suggest that Ahnak in glutamatergic PFC neurons may be critical for behavioral resilience and antidepressant actions of ketamine or HNK in chronic social stress-exposed mice.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"55 24","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140965623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dolutegravir induces FOLR1 expression during brain organoid development","authors":"Carlo Donato Caiaffa, Gabriel L Tukeman, Christian Zevallos Delgado, Yogeshwari S Ambekar, Taye Mekonnen, Manmohan Singh, Victoria Rodriguez, Emily Ricco, Daniel C. Kraushaar, S. Aglyamov, G. Scarcelli, K. Larin, Richard H. Finnell, Robert M. Cabrera","doi":"10.3389/fnmol.2024.1394058","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1394058","url":null,"abstract":"During the first month of pregnancy, the brain and spinal cord are formed through a process called neurulation. However, this process can be altered by low serum levels of folic acid, environmental factors, or genetic predispositions. In 2018, a surveillance study in Botswana, a country with a high incidence of human immunodeficiency virus (HIV) and lacking mandatory food folate fortification programs, found that newborns whose mothers were taking dolutegravir (DTG) during the first trimester of pregnancy had an increased risk of neural tube defects (NTDs). As a result, the World Health Organization and the U.S. Food and Drug Administration have issued guidelines emphasizing the potential risks associated with the use of DTG-based antiretroviral therapies during pregnancy. To elucidate the potential mechanisms underlying the DTG-induced NTDs, we sought to assess the potential neurotoxicity of DTG in stem cell-derived brain organoids. The gene expression of brain organoids developed in the presence of DTG was analyzed by RNA sequencing, Optical Coherence Tomography (OCT), Optical Coherence Elastography (OCE), and Brillouin microscopy. The sequencing data shows that DTG induces the expression of the folate receptor (FOLR1) and modifies the expression of genes required for neurogenesis. The Brillouin frequency shift observed at the surface of DTG-exposed brain organoids indicates an increase in superficial tissue stiffness. In contrast, reverberant OCE measurements indicate decreased organoid volumes and internal stiffness.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"53 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140965041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research trends of ferroptosis and pyroptosis in Parkinson’s disease: a bibliometric analysis","authors":"Zihua Wu, Kexin Zhong, Biao Tang, Sijian Xie","doi":"10.3389/fnmol.2024.1400668","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1400668","url":null,"abstract":"This study aims to visualize the trends and hotspots in the research of “ferroptosis in PD” and “pyroptosis in PD” through bibliometric analysis from the past to 2024.Literature was retrieved from the Web of Science Core Collection (WoSCC) from the past to February 16, 2024, and bibliometric analysis was conducted using Vosviewer and Citespace.283 and 542 papers were collected in the field of “ferroptosis in PD” and “pyroptosis in PD.” The number of publications in both fields has increased yearly, especially in “ferroptosis in PD,” which will become the focus of PD research. China, the United States and England had extensive exchanges and collaborations in both fields, and more than 60% of the top 10 institutions were from China. In the fields of “ferroptosis in PD” and “pyroptosis in PD,” the University of Melbourne and Nanjing Medical University stood out in terms of publication numbers, citation frequency, and centrality, and the most influential journals were Cell and Nature, respectively. The keyword time zone map showed that molecular mechanisms and neurons were the research hotspots of “ferroptosis in PD” in 2023, while memory and receptor 2 were the research hotspots of “pyroptosis in PD” in 2023, which may predict the future research direction.This study provides insights into the development, collaborations, research themes, hotspots, and tendencies of “ferroptosis in PD” and “pyroptosis in PD.” Overall situation of these fields is available for researchers to further explore the underlying mechanisms and potential treatments.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"28 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140967373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring AKAPs in visual signaling","authors":"Julia Tomczak, Joanna Mackiewicz, Malwina Lisek, Aleksandra Kaluza, T. Boczek","doi":"10.3389/fnmol.2024.1412407","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1412407","url":null,"abstract":"The complex nature of the retina demands well-organized signaling to uphold signal accuracy and avoid interference, a critical aspect in handling a variety of visual stimuli. A-kinase anchoring proteins (AKAPs), known for binding protein kinase A (PKA), contribute to the specificity and efficiency of retinal signaling. They play multifaceted roles in various retinal cell types, influencing photoreceptor sensitivity, neurotransmitter release in bipolar cells, and the integration of visual information in ganglion cells. AKAPs like AKAP79/150 and AKAP95 exhibit distinct subcellular localizations, impacting synaptic transmission and receptor sensitivity in photoreceptors and bipolar cells. Furthermore, AKAPs are involved in neuroprotective mechanisms and axonal degeneration, particularly in retinal ganglion cells. In particular, AKAP6 coordinates stress-specific signaling and promotes neuroprotection following optic nerve injury. As our review underscores the therapeutic potential of targeting AKAP signaling complexes for retinal neuroprotection and enhancement, it acknowledges challenges in developing selective drugs that target complex protein–protein interactions. Overall, this exploration of AKAPs provides valuable insights into the intricacies of retinal signaling, offering a foundation for understanding and potentially addressing retinal disorders.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"62 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140975402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acupuncture modulates the AMPK/PGC-1 signaling pathway to facilitate mitochondrial biogenesis and neural recovery in ischemic stroke rats","authors":"Kaixin Guo, Yan Lu","doi":"10.3389/fnmol.2024.1388759","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1388759","url":null,"abstract":"The main objective of this study was to investigate the role and mechanism of acupuncture on anti-nerve injury in the acute phase by regulating mitochondrial energy metabolism via monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) axis in rat ischemic stroke.Middle cerebral artery occlusion (MCAO) was established by middle cerebral artery occlusion/reperfusion. One-week of acupuncture was performed during the acute phase of ischemic stroke. The neurological function and brain tissue integrity were evaluated. Mitochondrial function (intracellular ATP level and the activity of mitochondrial respiratory chain complex I) and the level of NADH oxidase (NOX) were detected by enzymatic chemistry. Next, the potential molecular mechanisms were explored by western blotting, fluorescence quantitative PCR and immunohistochemistry method.(1) Acupuncture treatment for MCAO/R rats showed a significant improvement in the infarcted tissue accompanied by functional recovery in Zea-Longa score and balance beam score outcomes, motor function performances. (2) Acupuncture increased the levels of ATP and mitochondrial respiratory chain complex I, decreased the NOX levels in cerebral ischemia established by suture-occluded method. (3) Acupuncture reduced the necrosis dissolution of neuronal cells and meningeal edema, while promoting angiogenesis. (4) Quantitative immunohistochemical staining results showed acupuncture can increase the expression of AMPK, p-AMPK and the mitochondrial transcription factor PGC-1α, NRF2, TFAM and uncoupling protein 2 (UCP2). Meanwhile, acupuncture treatment up-regulated the expression of the corresponding protein. (5) Subsequently, acupuncture enhanced AMPK phosphorylation as well as the expression of PGC-1α, NRF2, TFAM and UCP2, implicated in mitochondrial synthesis and cellular apoptosis. (6) Finally, injections of AMPK antagonists and activators confirmed AMPK as a therapeutic target for the anti-nerve damage effects of acupuncture.Acupuncture intervention relieved ischemic stroke progression in MCAO rats by promoting energy metabolism and mitochondrial biogenesis in the brain and alleviating neuronal apoptosis, which was mediated by eliciting AMPK/PGC-1α axis, among them AMPK is a therapeutic target.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"80 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140973836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Horizontal-cell like Dm9 neurons in Drosophila modulate photoreceptor output to supply multiple functions in early visual processing","authors":"C. Schnaitmann, Manuel Pagni, Patrik B. Meyer, Lisa Steinhoff, Vitus Oberhauser, D. Reiff","doi":"10.3389/fnmol.2024.1347540","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1347540","url":null,"abstract":"Dm9 neurons in Drosophila have been proposed as functional homologs of horizontal cells in the outer retina of vertebrates. Here we combine genetic dissection of neuronal circuit function, two-photon calcium imaging in Dm9 and inner photoreceptors, and immunohistochemical analysis to reveal novel insights into the functional role of Dm9 in early visual processing. Our experiments show that Dm9 receive input from all four types of inner photoreceptor R7p, R7y, R8p, and R8y. Histamine released from all types R7/R8 directly inhibits Dm9 via the histamine receptor Ort, and outweighs simultaneous histamine-independent excitation of Dm9 by UV-sensitive R7. Dm9 in turn provides inhibitory feedback to all R7/R8, which is sufficient for color-opponent processing in R7 but not R8. Color opponent processing in R8 requires additional synaptic inhibition by R7 of the same ommatidium via axo-axonal synapses and the second Drosophila histamine receptor HisCl1. Notably, optogenetic inhibition of Dm9 prohibits color opponent processing in all types of R7/R8 and decreases intracellular calcium in photoreceptor terminals. The latter likely results from reduced release of excitatory glutamate from Dm9 and shifts overall photoreceptor sensitivity toward higher light intensities. In summary, our results underscore a key role of Dm9 in color opponent processing in Drosophila and suggest a second role of Dm9 in regulating light adaptation in inner photoreceptors. These novel findings on Dm9 are indeed reminiscent of the versatile functions of horizontal cells in the vertebrate retina.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"3 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140972842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroligin-1 dependent phosphotyrosine signaling in excitatory synapse differentiation","authors":"Zsófia Szíber, Adèle Drouet, Magali Mondin, Florian Levet, Olivier Thoumine","doi":"10.3389/fnmol.2024.1359067","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1359067","url":null,"abstract":"The synaptic adhesion molecule neuroligin-1 (NLGN1) is involved in the differentiation of excitatory synapses, but the precise underlying molecular mechanisms are still debated. Here, we explored the role of NLGN1 tyrosine phosphorylation in this process, focusing on a subset of receptor tyrosine kinases (RTKs), namely FGFR1 and Trks, that were previously described to phosphorylate NLGN1 at a unique intracellular residue (Y782).We used pharmacological inhibitors and genetic manipulation of those RTKs in dissociated hippocampal neurons, followed by biochemical measurement of NLGN1 phosphorylation and immunocytochemical staining of excitatory synaptic scaffolds.This study shows that: (i) the accumulation of PSD-95 at de novo NLGN1 clusters induced by neurexin crosslinking is reduced by FGFR and Trk inhibitors; (ii) the increase in PSD-95 puncta caused by NLGN1 over-expression is impaired by FGFR and Trk inhibitors; (iii) TrkB activation by BDNF increases NLGN1 phosphorylation; and (iv) TrkB knock-down impairs the increase of PSD-95 puncta caused by NLGN1 over-expression, an effect which is not seen with the NLGN1 Y782A mutant.Together, our data identify TrkB as one of the major RTKs responsible for NLGN1 tyrosine phosphorylation, and reveal that TrkB activity is necessary for the synaptogenic effects of NLGN1.","PeriodicalId":509130,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"60 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140972493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}