Amyloid-β oligomers suppress subunit-specific glutamate receptor increase during LTP

Introduction: Amyloid‐β oligomers (AβOs) are assumed to impair the ability of learning and memory by suppressing the induction of synaptic plasticity, such as long‐term potentiation (LTP) in the early stage of Alzheimer's disease. However, the direct molecular mechanism of how AβOs affect excitatory synaptic plasticity remains to be elucidated. Methods: In order to study the effects of AβOs on LTP‐associated changes of AMPA (alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid)‐type glutamate receptor (AMPAR) movement, we performed live‐cell imaging of fluorescently labeled AMPAR subunit GluA1 or GluA2 with total internal reflection fluorescence microscopy. Results: Incubation of cultured hippocampal neurons with AβOs for 1–2 days inhibited the increase in GluA1 number and GluA1 exocytosis frequency in both postsynaptic and extrasynaptic membranes during LTP. In contrast, AβOs did not inhibit the increase in GluA2 number or exocytosis frequency. Discussion: These results suggest that AβOs primarily inhibit the increase in the number of GluA1 homomers and suppress hippocampal LTP expression

Regulation of Dendritic Maintenance and Growth by a Mammalian 7-Pass Transmembrane Cadherin

AbstractDrosophila Flamingo is a 7-pass transmembrane cadherin that is necessary for dendritic patterning and axon guidance. How it works at the molecular level and whether homologs of Flamingo play similar roles in mammalian neurons or not have been unanswered questions. Here, we performed loss-of-function analysis using an RNAi system and organotypic brain slice cultures to address the role of a mammalian Flamingo homolog, Celsr2. Knocking down Celsr2 resulted in prominent simplification of dendritic arbors of cortical pyramidal neurons and Purkinje neurons, and this phenotype seemed to be due to branch retraction. Cadherin domain-mediated homophilic interaction appears to be required for the maintenance of dendritic branches. Furthermore, expression of various Celsr2 forms elicited distinct responses that were dependent on an extracellular subregion outside the cadherin domains and on a portion within the carboxyl intracellular tail. Based on these findings, we discuss how Celsr2 may regulate dendritic maintenance and growth

Prediction and validation of a mechanism to control the threshold for inhibitory synaptic plasticity

Synaptic plasticity, neuronal activity-dependent sustained alteration of the efficacy of synaptic transmission, underlies learning and memory. Activation of positive-feedback signaling pathways by an increase in intracellular Ca2+ concentration ([Ca2+]i) has been implicated in synaptic plasticity. However, the mechanism that determines the [Ca2+]i threshold for inducing synaptic plasticity is elusive. Here, we developed a kinetic simulation model of inhibitory synaptic plasticity in the cerebellum, and systematically analyzed the behavior of intricate molecular networks composed of protein kinases, phosphatases, etc. The simulation showed that Ca2+/calmodulin-dependent protein kinase II (CaMKII), which is essential for the induction of synaptic plasticity, was persistently activated or suppressed in response to different combinations of stimuli. The sustained CaMKII activation depended on synergistic actions of two positive-feedback reactions, CaMKII autophosphorylation and CaMKII-mediated inhibition of a CaM-dependent phosphodiesterase, PDE1. The simulation predicted that PDE1-mediated feedforward inhibition of CaMKII predominantly controls the Ca2+ threshold, which was confirmed by electrophysiological experiments in primary cerebellar cultures. Thus, combined application of simulation and experiments revealed that the Ca2+ threshold for the cerebellar inhibitory synaptic plasticity is primarily determined by PDE1

A reversible lesion of the corpus callosum splenium with adult influenza-associated encephalitis/encephalopathy: a case report

<p>ABstract</p> <p>Introduction</p> <p>Influenza virus-associated encephalitis/encephalopathy is a severe childhood illness with a poor prognosis. Adult case reports are rare and, to date, there have been no reports of adults with a mild subcortical encephalopathy with reversible lesions of the corpus callosum splenium.</p> <p>Case presentation</p> <p>A previously healthy 35-year-old man presented with acute progressive tetraplegia, transcortical motor aphasia and a mild decrease in his consciousness during his recovery after receiving oseltamivir phosphate treatment, and influenza type A antiviral medication. The initial magnetic resonance imaging study at day 1 showed symmetrical diffuse lesions in the white matter and a lesion on the central portion of the corpus callosum splenium. These findings had resolved on follow-up studies at day 8 and day 146. His neurological deficits mostly recovered within 12 hours following methylprednisolone pulse therapy. The levels of interleukin-6 and interleukin-10 in his blood and cerebrospinal fluid were initially elevated, but rapidly decreased to normal levels by day 8.</p> <p>Conclusion</p> <p>It is important for clinicians to recognize that even in adulthood, the subcortical encephalopathy observed during the therapeutic treatment for influenza type A infection can occur in conjunction with a reversible lesion of the corpus callosum, which may recover quickly. In addition, the cytokine storm in the blood system and the corticospinal cavity may play an important role in the etiology of the disease process.</p

Control of Cortical Axon Elongation by a GABA-Driven Ca<sup style="margin: 0px; padding: 0px; border: 0px; outline-style: none; font-weight: inherit; font-style: inherit; font-size: 0.85em; font-family: inherit; line-height: 0; text-align: inherit; vertical-align: super;">2+/Calmodulin-Dependent Protein Kinase Cascade</sup>

Ca(2+) signaling plays important roles during both axonal and dendritic growth. Yet, whether and how Ca(2+) rises may trigger and contribute to the development of long range cortical connections remains largely unknown. Here we demonstrate that two separate limbs of CaMK kinase (CaMKK) - CaMKI cascades, CaMKK-CaMKIα and CaMKK-CaMKIγ, critically coordinate axonal and dendritic morphogenesis of cortical neurons, respectively. The axon-specific morphological phenotype required a diffuse cytoplasmic localization and a strikingly α-isoform-specific kinase activity of CaMKI. Unexpectedly, treatment with muscimol, a GABA(A) receptor agonist, selectively stimulated elongation of axons but not of dendrites, and the CaMKK-CaMKIα cascade critically mediated this axonogenic effect. Consistent with these findings, during early brain development, in vivo knockdown of CaMKIα significantly impaired the terminal axonal extension, and thereby perturbed the refinement of the interhemispheric callosal projections into the contralateral cortices. Our findings thus indicate a novel role for the GABA-driven CaMKK-CaMKIα cascade as a mechanism critical for accurate cortical axon pathfinding, an essential process which may contribute to fine-tuning the formation of interhemispheric connectivity during the perinatal development of the central nervous system

Enhancement of Both Long-Term Depression Induction and Optokinetic Response Adaptation in Mice Lacking Delphilin

In the cerebellum, Delphilin is expressed selectively in Purkinje cells (PCs) and is localized exclusively at parallel fiber (PF) synapses, where it interacts with glutamate receptor (GluR) δ2 that is essential for long-term depression (LTD), motor learning and cerebellar wiring. Delphilin ablation exerted little effect on the synaptic localization of GluRδ2. There were no detectable abnormalities in cerebellar histology, PC cytology and PC synapse formation in contrast to GluRδ2 mutant mice. However, LTD induction was facilitated at PF-PC synapses in Delphilin mutant mice. Intracellular Ca2+ required for the induction of LTD appeared to be reduced in the mutant mice, while Ca2+ influx through voltage-gated Ca2+ channels and metabotropic GluR1-mediated slow synaptic response were similar between wild-type and mutant mice. We further showed that the gain-increase adaptation of the optokinetic response (OKR) was enhanced in the mutant mice. These findings are compatible with the idea that LTD induction at PF-PC synapses is a crucial rate-limiting step in OKR gain-increase adaptation, a simple form of motor learning. As exemplified in this study, enhancing synaptic plasticity at a specific synaptic site of a neural network is a useful approach to understanding the roles of multiple plasticity mechanisms at various cerebellar synapses in motor control and learning

Interleukin-6 Expression on the Biliary Epithelia During Inflammation-Associated Biliary Carcinogenesis in Bilioenterostomized Hamsters.

BACKGROUND: Chronic inflammatory conditions of the biliary tree strongly predispose patients to biliary carcinoma. The aim of this study was to evaluate the role of interleukin-6 (IL-6) expression during biliary carcinogenesis in bilioenterostomized hamsters. MATERIALS AND METHODS: Syrian hamsters were subjected to either a choledochoduodenostomy (CD, n=11) or a simple laparotomy (SL, n=10) and then received N-nitrosobis(2-oxopropyl)amine (BOP) treatment. The animals were sacrificed 20 wk after surgery and the development of biliary carcinoma, the presence and degree of cholangitis, and IL-6 expression on the biliary epithelia were examined histologically. RESULTS: In the CD group, eight hamsters (73%) demonstrated persistent cholangitis and six (55%) of them developed intrahepatic biliary carcinoma, while no hamster without cholangitis showed any biliary carcinoma. In the SL group, cholangitis was recognized in four hamsters (40%) and no development of biliary carcinoma was identified. A significantly high incidence of tumor development (P=0.024) and a close correlation between the presence of cholangitis and the occurrence of biliary carcinoma (P =0.013) were thus evident in the CD group. Moreover, the degree of cholangitis was significantly higher in the CD hamsters (P=0.041) and an IL-6 overexpression was identified in five hamsters that had undergone a CD, with a scattered expression on the intra- and extrahepatic biliary epithelia. Despite the fact that the induced biliary carcinomas showed a multicentric occurrence in the liver, these tumors originated from within the restricted area where IL-6 was expressed. CONCLUSIONS: A deregulated IL-6 overexpression on the biliary epithelia may therefore be involved in inflammation-associated biliary carcinogenesis in hamsters that have undergone a bilioenterostomy

miR-196a Downregulation Increases the Expression of Type I and III Collagens in Keloid Fibroblasts

Keloids are a fibroproliferative disease due to abnormal wound healing process after skin injury. They are characterized by overproduction of extracellular matrix (ECM) such as collagens. MicroRNAs (miRNAs) are noncoding small RNAs and negatively regulate protein expression. Several miRNAs that have critical roles in tissue fibrosis and ECM metabolism have been reported. However, regulation and function of miRNAs in keloid remain to be explored. The purpose of this study was to identify miRNAs involved in keloid pathogenesis. We performed miRNA microarray analysis to compare miRNA expression profiles between keloid-derived fibroblasts (KFs) and normal fibroblasts (NFs). In all, 7 upregulated and 20 downregulated miRNAs were identified. Among these, we focused on miR-196a, which showed the highest fold change. Overexpression or knockdown of miR-196a led to a decreased or increased level of secreted type I/III collagens, respectively. Reporter analysis showed direct binding of miR-196a to the 3′ untranslated region (UTR) of COL1A1 and COL3A1. In conclusion, we demonstrate for the first time that miRNA expression profile is altered in KFs compared with NFs. Downregulation of miR-196a may be one of the mechanisms by which collagens are highly deposited in keloid tissues. Our findings suggest that miR-196a could be a new therapeutic target for keloid lesions

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection