Article
Cell Biology
Achmed Mrestani, Martin Pauli, Philip Kollmannsberger, Felix Repp, Robert J. Kittel, Jens Eilers, Soren Doose, Markus Sauer, Anna-Leena Siren, Manfred Heckmann, Mila M. Paul
Summary: During PHP, individual AZs undergo compaction without changes in the copy numbers of AZ proteins. This compaction even occurs at the level of Brp subclusters and RBP subclusters, indicating a reorganization of AZ components. Correlative confocal and dSTORM imaging shows apparent increases in AZ area and Brp protein content during PHP.
Article
Neurosciences
Shankar Ramachandran, Shelagh Rodgriguez, Mariana Potcoava, Simon Alford
Summary: This study investigates the number, subtypes, and locations of Ca2+ channels involved in neurotransmitter release at central synapses. By using single channel analysis and lattice light-sheet microscopy, the researchers discovered that a small pool of Ca2+ channels, comprising N-, P/Q-, and R-subtypes, are available to gate neurotransmitter release. They also found that as few as one channel may trigger neurotransmitter release. These findings provide important insights into the understanding of Ca2+ channel and synaptic dysfunction.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Neurosciences
Iris Speigel, Kishan Patel, Vanessa Osman, Huge C. Hemmings Jr
Summary: Volatile anesthetics alter presynaptic function through effects on Ca2+ influx and neurotransmitter release, and this is mediated by the NO/cGMP signaling pathway. These findings provide new insights into the mechanisms of volatile anesthetics.
Article
Biochemical Research Methods
Jonathan W. Garcia, Thomas M. Bartol, Terrence J. Sejnowski
Summary: Chemical synapses exhibit a diverse array of internal mechanisms that affect the dynamics of transmission efficacy. Precise characterization of timing and probability of neurotransmitter release is necessary for constructing a phenomenologically realistic model. In this study, we obtained high-resolution profiles of instantaneous release rate by driving state vector models of synaptotagmin 1 and 7 with calcium traces obtained from a molecular MCell model. The results showed that synchronous and asynchronous release occur at different distances and the release rate curves decay exponentially with distance.
PLOS COMPUTATIONAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Fujun Luo, Alessandra Sclip, Sean Merrill, Thomas C. Sudhof
Summary: This study shows that neurexins are essential for the localization and function of presynaptic GABA(B)-receptor signaling complexes. Deletion of neurexins results in decreased sensitivity of neurotransmitter release to GABA(B)-receptor activation and loss of GABA(B)-receptors from the presynaptic active zone. Neurexins play a crucial role in regulating presynaptic GABA(B) receptors at multiple central nervous system synapses.
NATURE COMMUNICATIONS
(2021)
Review
Neurosciences
Karen L. Cunningham, J. Troy Littleton
Summary: Voltage-gated Ca2+ channels (VGCCs) play a crucial role in regulating neurotransmitter release at synapses. The abundance of VGCCs at active zones directly impacts synaptic strength. This article discusses the mechanisms involved in establishing VGCC abundance at synapses, including channel biosynthesis, axonal trafficking, incorporation and retention at presynaptic sites, and protein recycling, with insights from both invertebrate and vertebrate models.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Neurosciences
Yanfeng Zhang, Ting Wang, Yimei Cai, Tao Cui, Michelle Kuah, Stefano Vicini, Tingting Wang
Summary: This study explores the role of alpha 2 delta-3 in the homeostatic modulation of synaptic transmission. The results suggest that alpha 2 delta-3 regulates neurotransmitter release by controlling the localization of the calcium channel alpha 1 subunit at presynaptic release sites. Furthermore, two structural domains within alpha 2 delta-3 are found to play distinct roles in synaptic transmission and presynaptic calcium channel abundance.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Olga Tyurikova, Kaiyu Zheng, Elizabeth Nicholson, Yulia Timofeeva, Alexey Semyanov, Kirill E. Volynski, Dmitri A. Rusakov
Summary: In cortical pyramidal neurons, the amount of action potential-evoked Ca2+ entry tends to increase with the number of axonal branches, while the resting Ca2+ level remains stable. Inhibition of astroglial glutamate uptake reduces evoked Ca2+ entry but has minimal effect on resting Ca2+, whereas activation of group 1/2 metabotropic glutamate receptors enhances both. Transient somatic depolarization or hyperpolarization does not consistently affect presynaptic Ca2+ entry or its basal level. These findings provide insights into the basic principles of synaptic connectivity in the brain.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Biology
Shataakshi Dube O'Neil, Bence Racz, Walter Evan Brown, Yudong Gao, Erik J. Soderblom, Ryohei Yasuda, Scott H. Soderling
Summary: The study uncovers the contribution of activity-dependent cytoskeletal signaling to presynaptic plasticity, revealing that altering Rac1 pathway negatively regulates synaptic vesicle replenishment bidirectionally sculpting short-term synaptic depression. Using three independent approaches to manipulate presynaptic Rac1 activity, the study demonstrates a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across excitatory and inhibitory terminals.
Article
Cell Biology
Johannes Alexander Mueller, Julia Betzin, Jorge Santos-Tejedor, Annika Mayer, Ana-Maria Oprisoreanu, Kasper Engholm-Keller, Isabelle Paulussen, Polina Gulakova, Terrence Daniel McGovern, Lena Johanna Gschossman, Eva Schoenhense, Jesse R. Wark, Alf Lamprecht, Albert J. Becker, Ashley J. Waardenberg, Mark E. Graham, Dirk Dietrich, Susanne Schoch
Summary: The stability of synaptic function relies on the ability of synapses to adjust their strength according to neuronal activity levels. This study reveals that the phosphorylation status of the active-zone protein RIM1 is crucial for synaptic glutamate release. Furthermore, the protein kinase SRPK2 and RIM1 are shown to play a role in the homeostatic balance of synaptic coupling in neuronal networks.
Article
Cell Biology
Temitope Adeoye, Syed Shah, Angelo Demuro, David A. Rabson, Ghanim Ullah
Summary: The release of neurotransmitters is regulated by Ca2+ influx through voltage-gated Ca2+ channels at presynaptic terminals. The endoplasmic reticulum (ER) in neuronal axonal terminals plays a modulatory role in synaptic transmission by regulating Ca2+ levels. In familial Alzheimer's disease (FAD), enhanced Ca2+ release from the ER and downregulation of Ca2+ buffering proteins occur. This study investigates the impact of aberrant Ca2+ signaling on neurotransmitter release in FAD using computational modeling. The findings suggest that enhanced Ca2+ release increases the probability of neurotransmitter release in FAD, and it leads to activity-dependent short-term plasticity. However, during prolonged stimulation, pathological Ca2+ signaling causes depression and desynchronization, resulting in unreliable synaptic operation.
Article
Multidisciplinary Sciences
Murat Kirtay, Josefine Sell, Christian Marx, Holger Haselmann, Mihai Ceanga, Zhong-Wei Zhou, Vahid Rahmati, Joanna Kirkpatrick, Katrin Buder, Paulius Grigaravicius, Alessandro Ori, Christian Geis, Zhao-Qi Wang
Summary: ATR, a key regulator of DNA damage response and replication stress, also plays a role in regulating neuronal activity beyond its known functions. Deletion of ATR in neurons leads to increased intrinsic activity, aberrant firing, and heightened epileptiform activity, potentially increasing susceptibility to ataxia and epilepsy.
NATURE COMMUNICATIONS
(2021)
Review
Neurosciences
Filiz Sila Rizalar, Dorien A. Roosen, Volker Haucke
Summary: The authors reviewed the current understanding of the mechanisms governing the generation, transport, and assembly of key components for presynaptic neurotransmission, discussing how alterations in presynaptic assembly could impact nervous system function or lead to disease, and outlining key questions for future research.
Article
Multidisciplinary Sciences
Pei-Yi Lin, Lulu Y. Chen, Peng Zhou, Sung-Jin Lee, Justin H. Trotter, Thomas C. Suedhof
Summary: Recent research has shown that the deletion of Nrxn2 unexpectedly leads to an increase in excitatory synapse numbers and their presynaptic release probability, suggesting a role of Nrxn2 in restricting synapse assembly. Cultured hippocampal neurons have been used to study the synaptic function and mechanism of Nrxn2, revealing that certain splice variants of Nrxn2 restrict synapse numbers and restrain their release probability. These findings are significant for understanding the mechanism of synapse assembly.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biology
Martin Baccino-Calace, Katharina Schmidt, Martin Mueller
Summary: Synaptic proteins and synaptic transmission are regulated by homeostasis. The E3 ligase Thin plays a crucial role in presynaptic homeostatic plasticity, negatively regulating neurotransmitter release by limiting the number of release-ready vesicles. Thin controls release by degrading the schizophrenia-susceptibility gene Dysbindin, linking protein degradation to homeostatic regulation of neurotransmitter release.
Article
Geriatrics & Gerontology
Paula Juricic, Sebastian Groenke, Linda Partridge
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
(2020)
Article
Cell Biology
Luke S. Tain, Chirag Jain, Tobias Nespital, Jenny Froehlich, Yvonne Hinze, Sebastian Groenke, Linda Partridge
Article
Biochemical Research Methods
Parisa Kakanj, Sabine A. Eming, Linda Partridge, Maria Leptin
Review
Biotechnology & Applied Microbiology
Linda Partridge, Matias Fuentealba, Brian K. Kennedy
NATURE REVIEWS DRUG DISCOVERY
(2020)
Review
Biotechnology & Applied Microbiology
Maarouf Baghdadi, Helena M. Hinterding, Linda Partridge, Joris Deelen
Summary: Leading causes of death in humans, such as cardiovascular disease, type 2 diabetes, and Alzheimer's disease, are influenced by aging-related biological mechanisms. Studying genetic variants associated with aging can help uncover aging mechanisms and guide targeted interventions to improve health in old age.
BRIEFINGS IN FUNCTIONAL GENOMICS
(2022)
Article
Cell Biology
Matias Fuentealba, Daniel K. Fabian, Handan Melike Donertas, Janet M. Thornton, Linda Partridge
Summary: Genetically modified mouse models of ageing provide evidence that lifespan and healthspan can be influenced, with mutations affecting lifespan inducing similar transcriptomic changes. The study identified consistent gene expression changes in long-lived and short-lived mice, particularly in energy and lipid metabolism genes, suggesting accelerated ageing models partially reproduce molecular changes of aging. New genetic interventions were identified that may ameliorate ageing, by comparing the transcriptomes of mouse mutants with expression signatures of long-lived and short-lived mice.
MECHANISMS OF AGEING AND DEVELOPMENT
(2021)
Article
Biology
Yu-Xuan Lu, Jennifer C. Regan, Jacqueline Esser, Lisa F. Drews, Thomas Weinseis, Julia Stinn, Oliver Hahn, Richard A. Miller, Sebastian Gronke, Linda Partridge
Summary: Research shows that inhibition of mTORC1 by rapamycin increases the expression of histones H3 and H4 in intestinal enterocytes of Drosophila, leading to improved intestinal health and extended longevity. This finding suggests that the mTORC1-histone axis may be partially conserved in mammals, potentially offering new targets for anti-ageing interventions.
Article
Cell Biology
Tobias Nespital, Brit Neuhaus, Andrea Mesaros, Andre Pahl, Linda Partridge
Summary: Lithium shows a potential positive impact on health span in mice within a tolerable dose range, with caution needed for overdosing to avoid organ health issues.
Article
Cell Biology
Helen C. Fraser, Valerie Kuan, Ronja Johnen, Magdalena Zwierzyna, Aroon D. Hingorani, Andreas Beyer, Linda Partridge
Summary: This study found that interventions in the aging process can confer resistance to multiple age-related diseases in laboratory animals. By analyzing literature abstracts and clinical data, the researchers discovered associations between age-related diseases and aging mechanisms in humans. They also identified specific mechanisms that are associated with diverse age-related diseases. This suggests that targeting these mechanisms could potentially prevent multimorbidity.
Review
Cell Biology
Mihails Laskovs, Linda Partridge, Cathy Slack
Summary: The RAS/MAPK pathway plays a crucial role in cancer and is also associated with ageing. Decreasing RAS/MAPK signaling activity can extend lifespan, improve healthspan, and delay or prevent age-related functional decline. Evidence suggests that repurposing small molecule inhibitors of RAS/MAPK signaling can enhance health during ageing, but challenges need to be addressed before clinical implementation.
DISEASE MODELS & MECHANISMS
(2022)
Article
Multidisciplinary Sciences
Maarouf Baghdadi, Tobias Nespital, Andrea Mesaros, Sandra Buschbaum, Dominic J. Withers, Sebastian Gronke, Linda Partridge
Summary: Reduced insulin/insulin-like growth factor signaling (IIS) extends health and lifespan, but the exact tissues involved are unknown. This study found that lack of IRS1 in liver, muscle, or fat does not increase lifespan or improve health, but neuronal loss of IRS1 specifically in old males leads to improved health and metabolic adaptations consistent with activated stress response.
Article
Biology
Javier Moron-Oset, Lilly K. S. Fischer, Mireia Carcole, Ashling Giblin, Pingze Zhang, Adrian M. Isaacs, Sebastian Groenke, Linda Partridge
Summary: Hexanucleotide repeat expansions in the C9orf72 gene are the most prevalent genetic cause of amyotrophic lateral sclerosis frontotemporal dementia. Transcripts of the expansions translated into toxic dipeptide repeat (DPR) proteins. This study investigated the effects of protein tags on DPR toxicity using Drosophila.
LIFE SCIENCE ALLIANCE
(2023)
Article
Cell Biology
Carolina Monzo, Lisonia Gkioni, Andreas Beyer, Dario Riccardo Valenzano, Sebastian Gronke, Linda Partridge
Summary: Aging impairs immune function, but dietary restriction (DR) can attenuate this decline. In this study, it was shown that DR preserves B cell receptor (BCR) repertoire diversity and reduces clonal expansions during aging in mice. Remarkably, mice starting DR in mid-life have similar BCR diversity and clonal expansion rates as mice on chronic DR. These findings suggest a potential role of B cell repertoire dynamics in age-related health.
Article
Cell Biology
Jennifer C. Regan, Yu-Xuan Lu, Enric Urena, Ralf L. Meilenbrock, James H. Catterson, Disna Kissler, Jenny Froehlich, Emilie Funk, Linda Partridge
Summary: Pharmacological attenuation of mTOR presents a promising route for delay of age-related disease. In this study, the researchers found that the mTOR inhibitor rapamycin extends lifespan in female Drosophila by slowing down age-related gut pathology through increased autophagy. The study also reveals sexual dimorphism in enterocyte autophagy and response to rapamycin, which is conserved in mice.
Article
Neurosciences
Hrvoje Augustin, Asaph Zylbertal, Linda Partridge