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B Zhang, E Seigneur, P Wei, O Gokce, J Morgan, T C Südhof
Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Mutations in neuroligin-3 predispose to autism, but how such mutations affect synaptic function remains incompletely understood. Here we systematically examined the effect of three autism-associated mutations, the neuroligin-3 knockout, the R451C knockin, and the R704C knockin, on synaptic transmission in the calyx of Held, a central synapse ideally suited for high-resolution analyses of synaptic transmission. Surprisingly, germline knockout of neuroligin-3 did not alter synaptic transmission, whereas the neuroligin-3 R451C and R704C knockins decreased and increased, respectively, synaptic transmission...
October 11, 2016: Molecular Psychiatry
Yuko Fukata, Norihiko Yokoi, Yuri Miyazaki, Masaki Fukata
Physiological functioning of the brain requires fine-tuned synaptic transmission, and its dysfunction causes various brain disorders such as autism, dementia, and epilepsy. It is therefore extremely important to identify and characterize key regulators of synaptic function. In particular, disease-related synaptic proteins, such as autism-related neurexin-neuroligin and psychiatric disorder-related NMDA receptor, have attracted considerable attention. Recent basic and clinical research has highlighted critical roles of a ligand-receptor complex, LGI1-ADAM22, in synaptic transmission and brain function, as mutations in the LGI1 gene cause autosomal dominant lateral temporal lobe epilepsy and autoantibodies to LGI1 cause limbic encephalitis which is characterized by memory loss and seizures...
October 4, 2016: Neuroscience Research
Simon Früh, Jennifer Romanos, Patrizia Panzanelli, Daniela Bürgisser, Shiva K Tyagarajan, Kevin P Campbell, Mirko Santello, Jean-Marc Fritschy
: Distinct types of GABAergic interneurons target different subcellular domains of pyramidal cells, thereby shaping pyramidal cell activity patterns. Whether the presynaptic heterogeneity of GABAergic innervation is mirrored by specific postsynaptic factors is largely unexplored. Here we show that dystroglycan, a protein responsible for the majority of congenital muscular dystrophies when dysfunctional, has a function at postsynaptic sites restricted to a subset of GABAergic interneurons...
October 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Yusuke Naito, Alfred Kihoon Lee, Hideto Takahashi
Tropomyosin-receptor-kinase (Trk) receptors have been extensively studied for their roles in kinase-dependent signaling cascades in nervous system development. Synapse organization is coordinated by trans-synaptic interactions of various cell adhesion proteins, a representative example of which is the neurexin-neuroligin complex. Recently, a novel role for TrkC as a synapse organizing protein has been established. Post-synaptic TrkC binds to pre-synaptic type-IIa receptor-type protein tyrosine phosphatase sigma (PTPσ)...
September 30, 2016: Neuroscience Research
Xueshan Cao, Katsuhiko Tabuchi
Neurexins and neuroligins are two distinct families of single-pass transmembrane proteins localized at pre- and postsynapses, respectively. They trans-synaptically interact with each other and induce synapse formation and maturation. Common variants and rare mutations, including copy number variations, short deletions, and single or small nucleotide changes in neurexin and neuroligin genes have been linked to the neurodevelopmental disorders, such as autism spectrum disorders (ASDs). In this review, we summarize the structure and basic synaptic function of neurexins and neuroligins, followed by behaviors and synaptic phenotypes of knock-in and knock-out mouse of these family genes...
September 21, 2016: Neuroscience Research
Linda Soo Hoo, Chris D Banna, Carolyn M Radeke, Nikunj Sharma, Mary E Albertolle, Seng Hui Low, Thomas Weimbs, Carol A Vandenberg
Cell polarity and precise subcellular protein localization are pivotal to neuronal function. The SNARE machinery underlies intracellular membrane fusion events, but its role in neuronal polarity and selective protein targeting remain unclear. Here we report that syntaxin 3 is involved in orchestrating polarized trafficking in cultured rat hippocampal neurons. We show that syntaxin 3 localizes to the axonal plasma membrane, particularly to axonal tips, whereas syntaxin 4 localizes to the somatodendritic plasma membrane...
2016: PloS One
Zhuoyang Lu, M V V V Sekhar Reddy, Jianfang Liu, Ana Kalichava, Jiankang Liu, Lei Zhang, Fang Chen, Yun Wang, Luis Marcelo F Holthauzen, Mark A White, Suchithra Seshadrinathan, Xiaoying Zhong, Gang Ren, Gabby Rudenko
Contactin-associated protein-like 2 (CNTNAP2) is a large multi-domain neuronal adhesion molecule implicated in a number of neurological disorders, including epilepsy, schizophrenia, autistic spectrum disorder (ASD), intellectual disability, and language delay. We reveal here by electron microscopy that the architecture of CNTNAP2 is composed of a large, medium, and small lobe that flex with respect to each other. Using epitope labeling and fragments, we assign the F58C, L1, and L2 domains to the large lobe, the FBG and L3 domains to the middle lobe, and the L4 domain to the small lobe of the CNTNAP2 molecular envelop...
September 12, 2016: Journal of Biological Chemistry
Steven A Connor, Ina Ammendrup-Johnsen, Allen W Chan, Yasushi Kishimoto, Chiaki Murayama, Naokazu Kurihara, Atsushi Tada, Yuan Ge, Hong Lu, Ryan Yan, Jeffrey M LeDue, Hirotaka Matsumoto, Hiroshi Kiyonari, Yutaka Kirino, Fumio Matsuzaki, Toshiharu Suzuki, Timothy H Murphy, Yu Tian Wang, Tohru Yamamoto, Ann Marie Craig
Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses...
September 7, 2016: Neuron
Jeannine A Frei, Esther T Stoeckli
Many cell adhesion molecules are located at synapses but only few of them can be considered synaptic cell adhesion molecules in the strict sense. Besides the Neurexins and Neuroligins, the LRRTMs (leucine rich repeat transmembrane proteins) and the SynCAMs/CADMs can induce synapse formation when expressed in non-neuronal cells and therefore are true synaptic cell adhesion molecules. SynCAMs (synaptic cell adhesion molecules) are a subfamily of the immunoglobulin superfamily of cell adhesion molecules. As suggested by their name, they were first identified as cell adhesion molecules at the synapse which were sufficient to trigger synapse formation...
September 1, 2016: Molecular and Cellular Neurosciences
Ingrid Ehrmann, Philippe Fort, David J Elliott
STAR (signal transduction and activation of RNA) proteins regulate splicing of target genes that have roles in neural connectivity, survival and myelination in the vertebrate nervous system. These regulated splicing targets include mRNAs such as the Neurexins (Nrxn), SMN2 (survival of motor neuron) and MAG (myelin-associated glycoprotein). Recent work has made it possible to identify and validate STAR protein splicing targets in vivo by using genetically modified mouse models. In this review, we will discuss the importance of STAR protein splicing targets in the CNS (central nervous system)...
August 15, 2016: Biochemical Society Transactions
Jonathan Elegheert, Wataru Kakegawa, Jordan E Clay, Natalie F Shanks, Ester Behiels, Keiko Matsuda, Kazuhisa Kohda, Eriko Miura, Maxim Rossmann, Nikolaos Mitakidis, Junko Motohashi, Veronica T Chang, Christian Siebold, Ingo H Greger, Terunaga Nakagawa, Michisuke Yuzaki, A Radu Aricescu
Ionotropic glutamate receptor (iGluR) family members are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking postsynaptic iGluR δ2 (GluD2) and presynaptic β-neurexin 1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer...
July 15, 2016: Science
Gabriela Ramírez, Carol Fagundez, Juan P Grosso, Pablo Argibay, Andrés Arenas, Walter M Farina
In eusocial insects, experiences acquired during the development have long-term consequences on mature behavior. In the honeybee that suffers profound changes associated with metamorphosis, the effect of odor experiences at larval instars on the subsequent physiological and behavioral response is still unclear. To address the impact of preimaginal experiences on the adult honeybee, colonies containing larvae were fed scented food. The effect of the preimaginal experiences with the food odor was assessed in learning performance, memory retention and generalization in 3-5- and 17-19 day-old bees, in the regulation of their expression of synaptic-related genes and in the perception and morphology of their antennae...
2016: Frontiers in Behavioral Neuroscience
Koichi Kawada, Takaaki Iekumo, Masayuki Kaneko, Yasuyuki Nomura, Yasunobu Okuma
Neurodevelopmental disorders, which include autism spectrum disorder, are congenital impairments in the growth and development of the central nervous system. They are mainly accentuated during infancy and childhood. Autism spectrum disorder may be caused by environmental factors, genomic imprinting of chromosome 15q11-q13 regions, and gene defects such as those in genes encoding neurexin and neuroligin, which are involved in synaptogenesis and synaptic signaling. However, regardless of the many reports on neurodevelopmental disorders, the pathogenic mechanism and treatment of neurodevelopmental disorders remain unclear...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Jeffrey D Martell, Masahito Yamagata, Thomas J Deerinck, Sébastien Phan, Carolyn G Kwa, Mark H Ellisman, Joshua R Sanes, Alice Y Ting
Intercellular protein-protein interactions (PPIs) enable communication between cells in diverse biological processes, including cell proliferation, immune responses, infection, and synaptic transmission, but they are challenging to visualize because existing techniques have insufficient sensitivity and/or specificity. Here we report a split horseradish peroxidase (sHRP) as a sensitive and specific tool for the detection of intercellular PPIs. The two sHRP fragments, engineered through screening of 17 cut sites in HRP followed by directed evolution, reconstitute into an active form when driven together by an intercellular PPI, producing bright fluorescence or contrast for electron microscopy...
July 2016: Nature Biotechnology
Τao Zhu, Chen Liang, Dongdong Li, Miaomiao Tian, Sanxiong Liu, Guanjun Gao, Ji-Song Guan
Activity-dependent transcription is critical for the regulation of long-term synaptic plasticity and plastic rewiring in the brain. Here, we report that the transcription of neurexin1α (nrxn1α), a presynaptic adhesion molecule for synaptic formation, is regulated by transient neuronal activation. We showed that 10 minutes of firing at 50 Hz in neurons repressed the expression of nrxn1α for 24 hours in a primary cortical neuron culture through a transcriptional repression mechanism. By performing a screening assay using a synthetic zinc finger protein (ZFP) to pull down the proteins enriched near the nrxn1α promoter region in vivo, we identified that Ash1L, a histone methyltransferase, is enriched in the nrxn1α promoter...
2016: Scientific Reports
Elisabetta Furlanis, Peter Scheiffele
Regulation of neurotransmitter receptor localization is critical for synaptic function and plasticity. In this issue of Neuron, Matsuda and colleagues (Matsuda et al., 2016) uncover a transsynaptic complex consisting of neurexin-3, C1q-like proteins, and kainate receptors that drives glutamate receptor clustering at hippocampal synapses.
May 18, 2016: Neuron
Jin Hwan Lee, Alyssa R Espinera, Dongdong Chen, Ko-Eun Choi, Asha Yoshiko Caslin, Soonmi Won, Valentina Pecoraro, Guang-Yin Xu, Ling Wei, Shan Ping Yu
BACKGROUND: Autism spectrum disorder (ASD) affects many children and juveniles. The pathogenesis of ASD is not well understood. Environmental factors may play important roles in the development of ASD. We examined a possible relationship of inflammatory pain in neonates and the development of ASD in juveniles. METHODS: Acute inflammation pain was induced by 5 % formalin (5 μl/day) subcutaneous injection into two hindpaws of postnatal day 3 to 5 (P3-P5) rat pups...
2016: Journal of Neuroinflammation
Lisa Traunmüller, Andrea M Gomez, Thi-Minh Nguyen, Peter Scheiffele
Alternative RNA splicing represents a central mechanism for expanding the coding power of genomes. Individual RNA-binding proteins can control alternative splicing choices in hundreds of RNA transcripts, thereby tuning amounts and functions of large numbers of cellular proteins. We found that the RNA-binding protein SLM2 is essential for functional specification of glutamatergic synapses in the mouse hippocampus. Genome-wide mapping revealed a markedly selective SLM2-dependent splicing program primarily consisting of only a few target messenger RNAs that encode synaptic proteins...
May 20, 2016: Science
Nuria Gresa-Arribas, Jesús Planagumà, Mar Petit-Pedrol, Izumi Kawachi, Shinichi Katada, Carol A Glaser, Mateus M Simabukuro, Thaís Armangué, Eugenia Martínez-Hernández, Francesc Graus, Josep Dalmau
OBJECTIVE: To report a novel autoimmune encephalitis in which the antibodies target neurexin-3α, a cell adhesion molecule involved in the development and function of synapses. METHODS: Five patients with encephalitis and antibodies with a similar pattern of brain reactivity were selected. Antigen precipitation and determination of antibody effects on cultured rat embryonic neurons were performed with reported techniques. RESULTS: Immunoprecipitation and cell-based assays identified neurexin-3α as the autoantigen of patients' antibodies...
June 14, 2016: Neurology
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