Erika Taipala, Jeremiah C Pfitzer, Morgan Hellums, Miranda N Reed, Michael W Gramlich
{"title":"rTg(Tau<sub>P301L</sub>)4510 mice exhibit increased VGlut1 in hippocampal presynaptic glutamatergic vesicles and increased extracellular glutamate release.","authors":"Erika Taipala, Jeremiah C Pfitzer, Morgan Hellums, Miranda N Reed, Michael W Gramlich","doi":"10.3389/fnsyn.2022.925546","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.925546","url":null,"abstract":"<p><p>The molecular pathways that contribute to the onset of symptoms in tauopathy models, including Alzheimer's disease (AD), are difficult to distinguish because multiple changes can happen simultaneously at different stages of disease progression. Understanding early synaptic alterations and their supporting molecular pathways is essential to develop better pharmacological targets to treat AD. Here, we focus on an early onset rTg(Tau<sub>P301<i>L</i></sub> )4510 tauopathy mouse model that exhibits hyperexcitability in hippocampal neurons of adult mice that is correlated with presynaptic changes and increased extracellular glutamate levels. However, it is not clear if increased extracellular glutamate is caused by presynaptic changes alone, or if presynaptic changes are a contributing factor among other factors. To determine whether pathogenic tau alters presynaptic function and glutamate release, we studied cultured hippocampal neurons at 14-18 days <i>in vitro</i> (DIV) from animals of both sexes to measure presynaptic changes in tau<sub>P301L</sub> positive mice. We observed that presynaptic vesicles exhibit increased vesicular glutamate transporter 1 (VGlut1) using immunohistochemistry of fixed cells and an established pH-sensitive green fluorescent protein approach. We show that tau<sub>P301L</sub> positive neurons exhibit a 40% increase in VGlut1 per vesicle compared to tau<sub>P301L</sub> negative littermates. Further, we use the extracellular glutamate reporter iGluSnFR to show that increased VGlut1 per vesicle directly translates into a 40% increase in extracellular glutamate. Together, these results show that increased extracellular glutamate levels observed in tau<sub>P301L</sub> mice are not caused by increased vesicle exocytosis probability but rather are directly related to increased VGlut1 transporters per synaptic vesicle.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9383415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40713294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Barbara Barylko, Per Niklas Hedde, Clinton A Taylor, Derk D Binns, Yu-Kai Huang, Gemma Molinaro, Kimberly M Huber, David M Jameson, Joseph P Albanesi
{"title":"Palmitoylation-regulated interactions of the pseudokinase calmodulin kinase-like vesicle-associated with membranes and Arc/Arg3.1.","authors":"Barbara Barylko, Per Niklas Hedde, Clinton A Taylor, Derk D Binns, Yu-Kai Huang, Gemma Molinaro, Kimberly M Huber, David M Jameson, Joseph P Albanesi","doi":"10.3389/fnsyn.2022.926570","DOIUrl":"10.3389/fnsyn.2022.926570","url":null,"abstract":"<p><p>Calmodulin kinase-like vesicle-associated (CaMKv), a pseudokinase belonging to the Ca<sup>2+</sup>/calmodulin-dependent kinase family, is expressed predominantly in brain and neural tissue. It may function in synaptic strengthening during spatial learning by promoting the stabilization and enrichment of dendritic spines. At present, almost nothing is known regarding CaMKv structure and regulation. In this study we confirm prior proteomic analyses demonstrating that CaMKv is palmitoylated on Cys5. Wild-type CaMKv is enriched on the plasma membrane, but this enrichment is lost upon mutation of Cys5 to Ser. We further show that CaMKv interacts with another regulator of synaptic plasticity, Arc/Arg3.1, and that the interaction between these two proteins is weakened by mutation of the palmitoylated cysteine in CamKv.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40696434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Glucagon-like peptide 1 and glucose-dependent insulinotropic peptide hormones and novel receptor agonists protect synapses in Alzheimer's and Parkinson's diseases.","authors":"Christian Hölscher","doi":"10.3389/fnsyn.2022.955258","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.955258","url":null,"abstract":"<p><p>Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are peptide hormones and growth factors. A major pathological feature of both Alzheimer's dis-ease (AD) and Parkinson's disease (PD) is the loss of synaptic transmission in the cortex in AD and the loss of dopaminergic synapses in the nigra-striatal dopaminergic projection. Several studies demonstrate that GLP-1 and GIP receptor agonists protect synapses and synaptic transmission from the toxic events that underlie AD and PD. In a range of AD animal models, treatment with GLP-1, GIP, or dual-GLP-1/GIP receptor agonists effectively protected cognition, synaptic trans-mission, long-term potentiation (LTP), and prevented the loss of synapses and neurons. In PD models, dopaminergic production resumed and synapses became functional again. Importantly, the GLP-1 receptor agonists exendin-4 and liraglutide have shown good protective effects in clinical trials in AD and PD patients. Studies show that growth factors and peptide drugs that can cross the blood-brain barrier (BBB) better are more potent than those that do not cross the BBB. We therefore developed dual-GLP-1/GIP receptor agonists that can cross the BBB at an enhanced rate and showed superior protective properties on synapses in animal models of AD and PD.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9363704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40696435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Editorial: Regulation of AMPA Receptors, From the Genetic to the Functional Level.","authors":"Alberto Ouro, Tak Pan Wong, Laura Jiménez-Sánchez","doi":"10.3389/fnsyn.2022.952564","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.952564","url":null,"abstract":"the central and peripheral systems. They are in postsynaptic cells, but can also be found in pre-synaptic sites and glia processes. glutamate the postsynaptic AMPARs mediate the fast excitatory synaptic transmission which can be changed in an activity dependent manner and involve a minority of Ca 2 + permeable AMPARs. This Research Topic describes several new mechanisms that regulate AMPAR trafficking and plasticity;","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40556119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Corrigendum: Editorial: Activated Synapses.","authors":"F Javier Rubio, Emmanuel Valjent, Bruce T Hope","doi":"10.3389/fnsyn.2022.932503","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.932503","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fnsyn.2022.875904.].</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40580741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Astrocyte: A Foe or a Friend in Intellectual Disability-Related Diseases.","authors":"Busong Wang, Lu Zou, Min Li, Liang Zhou","doi":"10.3389/fnsyn.2022.877928","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.877928","url":null,"abstract":"<p><p>Intellectual disabilities are a type of neurodevelopmental disease caused by neurological dysfunction. Their incidence is largely associated with neural development. Astrocytes are the most widely distributed cells in the mammalian brain. Previous studies have reported that astrocytes only supported and separated the neurons in the brain. However, recent studies have found that they also play an important role in neural development. Understanding the astrocyte mechanism in intellectual development disorder-related diseases will help provide new therapeutic targets for the treatment of intellectual disability-related diseases. This mini-review introduced the association between astrocyte and intellectual disabilities. Furthermore, recent advances in genetic and environmental factors causing intellectual disability and different pharmaceutical effects of intellectual disability-related drugs on astrocytes have been summarised. Finally, we discussed future perspectives of astrocyte-based therapy for intellectual disability.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40603771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Corrigendum: Correlative Live-Cell and Super-Resolution Imaging to Link Presynaptic Molecular Organisation With Function.","authors":"Rachel E Jackson, Benjamin Compans, Juan Burrone","doi":"10.3389/fnsyn.2022.953045","DOIUrl":"10.3389/fnsyn.2022.953045","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fnsyn.2022.830583.].</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40467350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Regulation of Inhibitory Signaling at the Receptor and Cellular Level; Advances in Our Understanding of GABAergic Neurotransmission and the Mechanisms by Which It Is Disrupted in Epilepsy.","authors":"Allison E Tipton, Shelley J Russek","doi":"10.3389/fnsyn.2022.914374","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.914374","url":null,"abstract":"<p><p>Inhibitory signaling in the brain organizes the neural circuits that orchestrate how living creatures interact with the world around them and how they build representations of objects and ideas. Without tight control at multiple points of cellular engagement, the brain's inhibitory systems would run down and the ability to extract meaningful information from excitatory events would be lost leaving behind a system vulnerable to seizures and to cognitive decline. In this review, we will cover many of the salient features that have emerged regarding the dynamic regulation of inhibitory signaling seen through the lens of cell biology with an emphasis on the major building blocks, the ligand-gated ion channel receptors that are the first transduction point when the neurotransmitter GABA is released into the synapse. Epilepsy association will be used to indicate importance of key proteins and their pathways to brain function and to introduce novel areas for therapeutic intervention.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40645333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Microphysiological Modeling of the Structure and Function of Neuromuscular Transmitter Release Sites.","authors":"Rozita Laghaei, Stephen D Meriney","doi":"10.3389/fnsyn.2022.917285","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.917285","url":null,"abstract":"<p><p>The general mechanism of calcium-triggered chemical transmitter release from neuronal synapses has been intensely studied, is well-known, and highly conserved between species and synapses across the nervous system. However, the structural and functional details within each transmitter release site (or active zone) are difficult to study in living tissue using current experimental approaches owing to the small spatial compartment within the synapse where exocytosis occurs with a very rapid time course. Therefore, computer simulations offer the opportunity to explore these microphysiological environments of the synapse at nanometer spatial scales and on a sub-microsecond timescale. Because biological reactions and physiological processes at synapses occur under conditions where stochastic behavior is dominant, simulation approaches must be driven by such stochastic processes. MCell provides a powerful simulation approach that employs particle-based stochastic simulation tools to study presynaptic processes in realistic and complex (3D) geometries using optimized Monte Carlo algorithms to track finite numbers of molecules as they diffuse and interact in a complex cellular space with other molecules in solution and on surfaces (representing membranes, channels and binding sites). In this review we discuss MCell-based spatially realistic models of the mammalian and frog neuromuscular active zones that were developed to study presynaptic mechanisms that control transmitter release. In particular, these models focus on the role of presynaptic voltage-gated calcium channels, calcium sensors that control the probability of synaptic vesicle fusion, and the effects of action potential waveform shape on presynaptic calcium entry. With the development of these models, they can now be used in the future to predict disease-induced changes to the active zone, and the effects of candidate therapeutic approaches.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9236679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40405537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caroline A Browne, Katherine Conant, Amy W Lasek, Juan Nacher
{"title":"Editorial: Perineuronal Nets as Therapeutic Targets for the Treatment of Neuropsychiatric Disorders.","authors":"Caroline A Browne, Katherine Conant, Amy W Lasek, Juan Nacher","doi":"10.3389/fnsyn.2022.889800","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.889800","url":null,"abstract":"","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40467351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}