Shigeki Watanabe, M Wayne Davis, Grant F Kusick, Janet Iwasa, Erik M Jorgensen
{"title":"SynapsEM: Computer-Assisted Synapse Morphometry.","authors":"Shigeki Watanabe, M Wayne Davis, Grant F Kusick, Janet Iwasa, Erik M Jorgensen","doi":"10.3389/fnsyn.2020.584549","DOIUrl":"https://doi.org/10.3389/fnsyn.2020.584549","url":null,"abstract":"<p><p>The structural features of a synapse help determine its function. Synapses are extremely small and tightly packed with vesicles and other organelles. Visualizing synaptic structure requires imaging by electron microscopy, and the features in micrographs must be quantified, a process called morphometry. Three parameters are typically assessed from each specimen: (1) the sizes of individual vesicles and organelles; (2) the absolute number and densities of organelles; and (3) distances between organelles and key features at synapses, such as active zone membranes and dense projections. For data to be meaningful, the analysis must be repeated from hundreds to thousands of images from several biological replicates, a daunting task. Here we report a custom computer program to analyze key structural features of synapses: SynapsEM. In short, we developed ImageJ/Fiji macros to record x,y-coordinates of segmented structures. The coordinates are then exported as text files. Independent investigators can reload the images and text files to reexamine the segmentation using ImageJ. The Matlab program then calculates and reports key synaptic parameters from the coordinates. Since the values are calculated from coordinates, rather than measured from each micrograph, other parameters such as locations of docked vesicles relative to the center of an active zone can be extracted in Matlab by additional scripting. Thus, this program can accelerate the morphometry of synapses and promote a more comprehensive analysis of synaptic ultrastructure.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"584549"},"PeriodicalIF":3.7,"publicationDate":"2020-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3389/fnsyn.2020.584549","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38776094","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}
Emma Arvidsson, Sarolta Gabulya, Alvin Tore Brodin, Tobias Erik Karlsson, Lars Olson
{"title":"Forebrain NgR1 Overexpression Impairs DA Release Suggesting Synergy of Local and Global Synaptic Plasticity Mechanisms.","authors":"Emma Arvidsson, Sarolta Gabulya, Alvin Tore Brodin, Tobias Erik Karlsson, Lars Olson","doi":"10.3389/fnsyn.2020.545854","DOIUrl":"https://doi.org/10.3389/fnsyn.2020.545854","url":null,"abstract":"<p><p>Structural synaptic reorganizations needed to permanently embed novel memories in the brain involve complex plasticity-enhancing and plasticity-inhibiting systems. Increased neural activity is linked to rapid downregulation of Nogo receptor 1 (NgR1), needed to allow local structural synaptic plasticity. This local regulation of plasticity is thought to be moderated by global systems, such as the ascending cholinergic and monoaminergic systems, adding significance to locally increased neural activity. Here we address the reverse possibility that the global systems may also be influenced by the status of local plasticity. Using NgR1-overexpressing mice, with impaired plasticity and long-term memory, we measured the ability to release dopamine (DA), implicated in regulating plasticity and memory. <i>In vivo</i> chronoamperometric recording with high temporal and spatial resolution revealed severe impairment of potassium chloride (KCl)-induced increase of extracellular DA in the dorsal striatum of mice overexpressing NgR1 in forebrain neurons. A similar, but lesser, impairment of DA release was seen following amphetamine delivery. In contrast, potassium chloride-evoked DA release in NgR1 knockout (KO) mice led to increased levels of extracellular DA. That NgR1 can impair DA signaling, thereby further dampening synaptic plasticity, suggests a new role for NgR1 signaling, acting in synergy with DA signaling to control synaptic plasticity. <b>Significance Statement:</b>The inverse correlation between local NgR1 levels and magnitude of KCl-inducible amounts of DA release in the striatum reinforces the rule of NgR1 as a regulator of structural synaptic plasticity and suggests synergy between local and global plasticity regulating systems.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"545854"},"PeriodicalIF":3.7,"publicationDate":"2020-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3389/fnsyn.2020.545854","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38750223","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":"Transient Enhanced GluA2 Expression in Young Hippocampal Neurons of a Fragile X Mouse Model.","authors":"Tue G Banke, Andres Barria","doi":"10.3389/fnsyn.2020.588295","DOIUrl":"https://doi.org/10.3389/fnsyn.2020.588295","url":null,"abstract":"<p><p>AMPA-type glutamate receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits and play important roles in synaptic transmission and plasticity. Here, we have investigated the development of AMPAR-mediated synaptic transmission in the hippocampus of the Fmr1 knock-out (KO) mouse, a widely used model of Fragile X syndrome (FXS). FXS is the leading monogenic cause of intellectual disability and autism spectrum disorders (ASD) and it is considered a neurodevelopmental disorder. For that reason, we investigated synaptic properties and dendritic development in animals from an early stage when synapses are starting to form up to adulthood. We found that hippocampal CA1 pyramidal neurons in the Fmr1-KO mouse exhibit a higher AMPAR-NMDAR ratio early in development but reverses to normal values after P13. This increase was accompanied by a larger presence of the GluA2-subunit in synaptic AMPARs that will lead to altered Ca<sup>2+</sup> permeability of AMPARs that could have a profound impact upon neural circuits, learning, and diseases. Following this, we found that young KO animals lack Long-term potentiation (LTP), a well-understood model of synaptic plasticity necessary for proper development of circuits, and exhibit an increased frequency of spontaneous miniature excitatory postsynaptic currents, a measure of synaptic density. Furthermore, <i>post hoc</i> morphological analysis of recorded neurons revealed altered dendritic branching in the KO group. Interestingly, all these anomalies are transitory and revert to normal values in older animals. Our data suggest that loss of FMRP during early development leads to temporary upregulation of the GluA2 subunit and this impacts synaptic plasticity and altering morphological dendritic branching.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"588295"},"PeriodicalIF":3.7,"publicationDate":"2020-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3389/fnsyn.2020.588295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38731107","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":"The α5 Nicotinic Acetylcholine Receptor Subunit Differentially Modulates α4β2<sup>*</sup> and α3β4<sup>*</sup> Receptors.","authors":"Petra Scholze, Sigismund Huck","doi":"10.3389/fnsyn.2020.607959","DOIUrl":"https://doi.org/10.3389/fnsyn.2020.607959","url":null,"abstract":"<p><p>Nicotine, the principal reinforcing compound in tobacco, acts in the brain by activating neuronal nicotinic acetylcholine receptors (nAChRs). This review summarizes our current knowledge regarding how the α5 accessory nAChR subunit, encoded by the <i>CHRNA5</i> gene, differentially modulates α4β2<sup>*</sup> and α3β4<sup>*</sup> receptors at the cellular level. Genome-wide association studies have linked a gene cluster in chromosomal region 15q25 to increased susceptibility to nicotine addiction, lung cancer, chronic obstructive pulmonary disease, and peripheral arterial disease. Interestingly, this gene cluster contains a non-synonymous single-nucleotide polymorphism (SNP) in the human <i>CHRNA5</i> gene, causing an aspartic acid (D) to asparagine (N) substitution at amino acid position 398 in the α5 nAChR subunit. Although other SNPs have been associated with tobacco smoking behavior, efforts have focused predominantly on the D398 and N398 variants in the α5 subunit. In recent years, significant progress has been made toward understanding the role that the α5 nAChR subunit-and the role of the D398 and N398 variants-plays on nAChR function at the cellular level. These insights stem primarily from a wide range of experimental models, including receptors expressed heterologously in <i>Xenopus</i> oocytes, various cell lines, and neurons derived from human induced pluripotent stem cells (iPSCs), as well as endogenous receptors in genetically engineered mice and-more recently-rats. Despite providing a wealth of available data, however, these studies have yielded conflicting results, and our understanding of the modulatory role that the α5 subunit plays remains incomplete. Here, we review these reports and the various techniques used for expression and analysis in order to examine how the α5 subunit modulates key functions in α4β2<sup>*</sup> and α3β4<sup>*</sup> receptors, including receptor trafficking, sensitivity, efficacy, and desensitization. In addition, we highlight the strikingly different role that the α5 subunit plays in Ca<sup>2+</sup> signaling between α4β2<sup>*</sup> and α3β4<sup>*</sup> receptors, and we discuss whether the N398 α5 subunit variant can partially replace the D398 variant.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"607959"},"PeriodicalIF":3.7,"publicationDate":"2020-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3389/fnsyn.2020.607959","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38731108","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}
Tiffany Ona Jodar, Vanessa Lage-Rupprecht, Nixon M Abraham, Christine R Rose, Veronica Egger
{"title":"Local Postsynaptic Signaling on Slow Time Scales in Reciprocal Olfactory Bulb Granule Cell Spines Matches Asynchronous Release.","authors":"Tiffany Ona Jodar, Vanessa Lage-Rupprecht, Nixon M Abraham, Christine R Rose, Veronica Egger","doi":"10.3389/fnsyn.2020.551691","DOIUrl":"10.3389/fnsyn.2020.551691","url":null,"abstract":"<p><p>In the vertebrate olfactory bulb (OB), axonless granule cells (GC) mediate self- and lateral inhibitory interactions between mitral/tufted cells via reciprocal dendrodendritic synapses. Locally triggered release of GABA from the large reciprocal GC spines occurs on both fast and slow time scales, possibly enabling parallel processing during olfactory perception. Here we investigate local mechanisms for asynchronous spine output. To reveal the temporal and spatial characteristics of postsynaptic ion transients, we imaged spine and adjacent dendrite Ca<sup>2 +</sup>- and Na<sup>+</sup>-signals with minimal exogenous buffering by the respective fluorescent indicator dyes upon two-photon uncaging of DNI-glutamate in OB slices from juvenile rats. Both postsynaptic fluorescence signals decayed slowly, with average half durations in the spine head of t<sub>1</sub> <sub>/</sub> <sub>2</sub>_Δ[Ca<sup>2 +</sup>]<sub>i</sub> ∼500 ms and t<sub>1</sub> <sub>/</sub> <sub>2</sub>_Δ[Na<sup>+</sup>]<sub>i</sub> ∼1,000 ms. We also analyzed the kinetics of already existing data of postsynaptic spine Ca<sup>2 +</sup>-signals in response to glomerular stimulation in OB slices from adult mice, either WT or animals with partial GC glutamate receptor deletions (NMDAR: GluN1 subunit; AMPAR: GluA2 subunit). In a large subset of spines the fluorescence signal had a protracted rise time (average time to peak ∼400 ms, range 20 to >1,000 ms). This slow rise was independent of Ca<sup>2 +</sup> entry via NMDARs, since similarly slow signals occurred in ΔGluN1 GCs. Additional Ca<sup>2 +</sup> entry in ΔGluA2 GCs (with AMPARs rendered Ca<sup>2 +</sup>-permeable), however, resulted in larger ΔF/Fs that rose yet more slowly. Thus GC spines appear to dispose of several local mechanisms to promote asynchronous GABA release, which are reflected in the time course of mitral/tufted cell recurrent inhibition.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"551691"},"PeriodicalIF":3.7,"publicationDate":"2020-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3389/fnsyn.2020.551691","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38709762","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":"Dendritic Voltage Recordings Explain Paradoxical Synaptic Plasticity: A Modeling Study.","authors":"Claire Meissner-Bernard, Matthias Chinyen Tsai, Laureline Logiaco, Wulfram Gerstner","doi":"10.3389/fnsyn.2020.585539","DOIUrl":"https://doi.org/10.3389/fnsyn.2020.585539","url":null,"abstract":"<p><p>Experiments have shown that the same stimulation pattern that causes Long-Term Potentiation in proximal synapses, will induce Long-Term Depression in distal ones. In order to understand these, and other, surprising observations we use a phenomenological model of Hebbian plasticity at the location of the synapse. Our model describes the Hebbian condition of joint activity of pre- and postsynaptic neurons in a compact form as the interaction of the glutamate trace left by a presynaptic spike with the time course of the postsynaptic voltage. Instead of simulating the voltage, we test the model using experimentally recorded dendritic voltage traces in hippocampus and neocortex. We find that the time course of the voltage in the neighborhood of a stimulated synapse is a reliable predictor of whether a stimulated synapse undergoes potentiation, depression, or no change. Our computational model can explain the existence of different -at first glance seemingly paradoxical- outcomes of synaptic potentiation and depression experiments depending on the dendritic location of the synapse and the frequency or timing of the stimulation.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"585539"},"PeriodicalIF":3.7,"publicationDate":"2020-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38629866","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}
An Liu, Hong Ji, Qiaoyun Ren, Yanghong Meng, Haiwang Zhang, Graham Collingride, Wei Xie, Zhengping Jia
{"title":"The Requirement of the C-Terminal Domain of GluA1 in Different Forms of Long-Term Potentiation in the Hippocampus Is Age-Dependent.","authors":"An Liu, Hong Ji, Qiaoyun Ren, Yanghong Meng, Haiwang Zhang, Graham Collingride, Wei Xie, Zhengping Jia","doi":"10.3389/fnsyn.2020.588785","DOIUrl":"https://doi.org/10.3389/fnsyn.2020.588785","url":null,"abstract":"<p><p>Long-term potentiation (LTP) at glutamatergic synapses is an extensively studied form of long-lasting synaptic plasticity widely regarded as the cellular basis for learning and memory. At the CA1 synapse, there are multiple forms of LTP with distinct properties. Although AMPA glutamate receptors (AMPARs) are a key target of LTP expression, whether they are required in all forms of LTP remains unclear. To address this question, we have used our recently developed mouse line, GluA1 <sup><i>C2KI</i></sup> , where the c-terminal domain (CTD) of the endogenous GluA1 is replaced by that of GluA2. Unlike traditional GluA1 global or conditional KO mice, GluA1 <sup><i>C2KI</i></sup> mice have no changes in basal AMPAR properties or synaptic transmission allowing a better assessment of GluA1 in synaptic plasticity. We previously showed that these mice are impaired in LTP induced by high-frequency stimulation (HFS-LTP), but whether other forms of LTP are also affected in these mice is unknown. In this study, we compared various forms of LTP at CA1 synapses between GluA1 <sup><i>C2KI</i></sup> and wild-type littermates by using several induction protocols. We show that HFS-LTP is impaired in both juvenile and adult GluA1 <sup><i>C2KI</i></sup> mice. The LTP induced by theta-burst stimulation (TBS-LTP) is also abolished in juvenile GluA1 <sup><i>C2KI</i></sup> mice. Interestingly, TBS-LTP can still be induced in adult GluA1 <sup><i>C2KI</i></sup> mice, but its mechanisms are altered becoming more sensitive to protein synthesis and the extracellular signal-regulated kinase (ERK) inhibitors compared to wild type (WT) control. The GluA1 <sup><i>C2KI</i></sup> mice are also differentially altered in several forms of LTP induced under whole-cell recording paradigms. These results indicate that the CTD of GluA1 is differentially involved in different forms of LTP at CA1 synapse highlighting the complexity and adaptative potential of LTP expression mechanisms in the hippocampus.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"588785"},"PeriodicalIF":3.7,"publicationDate":"2020-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3389/fnsyn.2020.588785","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38605186","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}
Eva Maria Fritz, Nicolas Singewald, Dimitri De Bundel
{"title":"The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders.","authors":"Eva Maria Fritz, Nicolas Singewald, Dimitri De Bundel","doi":"10.3389/fnsyn.2020.594484","DOIUrl":"https://doi.org/10.3389/fnsyn.2020.594484","url":null,"abstract":"<p><p>Ghrelin is a peptide hormone released by specialized X/A cells in the stomach and activated by acylation. Following its secretion, it binds to ghrelin receptors in the periphery to regulate energy balance, but it also acts on the central nervous system where it induces a potent orexigenic effect. Several types of stressors have been shown to stimulate ghrelin release in rodents, including nutritional stressors like food deprivation, but also physical and psychological stressors such as foot shocks, social defeat, forced immobilization or chronic unpredictable mild stress. The mechanism through which these stressors drive ghrelin release from the stomach lining remains unknown and, to date, the resulting consequences of ghrelin release for stress coping remain poorly understood. Indeed, ghrelin has been proposed to act as a stress hormone that reduces fear, anxiety- and depression-like behaviors in rodents but some studies suggest that ghrelin may - in contrast - promote such behaviors. In this review, we aim to provide a comprehensive overview of the literature on the role of the ghrelin system in stress coping. We discuss whether ghrelin release is more than a byproduct of disrupted energy homeostasis following stress exposure. Furthermore, we explore the notion that ghrelin receptor signaling in the brain may have effects independent of circulating ghrelin and in what way this might influence stress coping in rodents. Finally, we examine how the ghrelin system could be utilized as a therapeutic avenue in stress-related psychiatric disorders (with a focus on anxiety- and trauma-related disorders), for example to develop novel biomarkers for a better diagnosis or new interventions to tackle relapse or treatment resistance in patients.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"594484"},"PeriodicalIF":3.7,"publicationDate":"2020-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3389/fnsyn.2020.594484","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38602682","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: Psychedelics as a Treatment for Alzheimer's Disease Dementia.","authors":"Simon Andrew Vann Jones, Allison O'Kelly","doi":"10.3389/fnsyn.2020.607194","DOIUrl":"https://doi.org/10.3389/fnsyn.2020.607194","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fnsyn.2020.00034.].</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"607194"},"PeriodicalIF":3.7,"publicationDate":"2020-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3389/fnsyn.2020.607194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38602681","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}
Clemens V Farr, Ali El-Kasaby, Michael Freissmuth, Sonja Sucic
{"title":"The Creatine Transporter Unfolded: A Knotty Premise in the Cerebral Creatine Deficiency Syndrome.","authors":"Clemens V Farr, Ali El-Kasaby, Michael Freissmuth, Sonja Sucic","doi":"10.3389/fnsyn.2020.588954","DOIUrl":"10.3389/fnsyn.2020.588954","url":null,"abstract":"<p><p>Creatine provides cells with high-energy phosphates for the rapid reconstitution of hydrolyzed adenosine triphosphate. The eponymous creatine transporter (CRT1/SLC6A8) belongs to a family of solute carrier 6 (SLC6) proteins. The key role of CRT1 is to translocate creatine across tissue barriers and into target cells, such as neurons and myocytes. Individuals harboring mutations in the coding sequence of the human CRT1 gene develop creatine transporter deficiency (CTD), one of the pivotal underlying causes of cerebral creatine deficiency syndrome. CTD encompasses an array of clinical manifestations, including severe intellectual disability, epilepsy, autism, development delay, and motor dysfunction. CTD is characterized by the absence of cerebral creatine, which implies an indispensable role for CRT1 in supplying the brain cells with creatine. CTD-associated variants dramatically reduce or abolish creatine transport activity by CRT1. Many of these are point mutations that are known to trigger folding defects, leading to the retention of encoded CRT1 proteins in the endoplasmic reticulum and precluding their delivery to the cell surface. Misfolding of several related SLC6 transporters also gives rise to detrimental pathologic conditions in people; e.g., mutations in the dopamine transporter induce infantile parkinsonism/dystonia, while mutations in the GABA transporter 1 cause treatment-resistant epilepsy. In some cases, folding defects are amenable to rescue by small molecules, known as pharmacological and chemical chaperones, which restore the cell surface expression and transport activity of the previously non-functional proteins. Insights from the recent molecular, animal and human case studies of CTD add toward our understanding of this complex disorder and reveal the wide-ranging effects elicited upon CRT1 dysfunction. This grants novel therapeutic prospects for the treatment of patients afflicted with CTD, e.g., modifying the creatine molecule to facilitate CRT1-independent entry into brain cells, or correcting folding-deficient and loss-of-function CTD variants using pharmacochaperones and/or allosteric modulators. The latter justifies a search for additional compounds with a capacity to correct mutation-specific defects.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"12 ","pages":"588954"},"PeriodicalIF":3.7,"publicationDate":"2020-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3389/fnsyn.2020.588954","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38602680","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}