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https://www.readbyqxmd.com/read/27909399/a-subset-of-autism-associated-genes-regulate-the-structural-stability-of-neurons
#1
REVIEW
Yu-Chih Lin, Jeannine A Frei, Michaela B C Kilander, Wenjuan Shen, Gene J Blatt
Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals' ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27905548/neurexin-regulates-nighttime-sleep-by-modulating-synaptic-transmission
#2
Huawei Tong, Qian Li, Zi Chao Zhang, Yi Li, Junhai Han
Neurexins are cell adhesion molecules involved in synaptic formation and synaptic transmission. Mutations in neurexin genes are linked to autism spectrum disorders (ASDs), which are frequently associated with sleep problems. However, the role of neurexin-mediated synaptic transmission in sleep regulation is unclear. Here, we show that lack of the Drosophila α-neurexin homolog significantly reduces the quantity and quality of nighttime sleep and impairs sleep homeostasis. We report that neurexin expression in Drosophila mushroom body (MB) αβ neurons is essential for nighttime sleep...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27872870/nanoscale-organization-of-synaptic-adhesion-proteins-revealed-by-single-molecule-localization-microscopy
#3
Ingrid Chamma, Florian Levet, Jean-Baptiste Sibarita, Matthieu Sainlos, Olivier Thoumine
The advent of superresolution imaging has created a strong need for both optimized labeling strategies and analysis methods to probe the nanoscale organization of complex biological structures. We present a thorough description of the distribution of synaptic adhesion proteins at the nanoscopic scale, namely presynaptic neurexin-[Formula: see text] ([Formula: see text]), and its two postsynaptic binding partners neuroligin-1 (Nlg1) and leucine-rich-repeat transmembrane protein 2 (LRRTM2). We monitored these proteins in the membrane of neurons by direct stochastic optical reconstruction microscopy, after live surface labeling with Alexa647-conjugated monomeric streptavidin...
October 2016: Neurophotonics
https://www.readbyqxmd.com/read/27871938/the-role-of-gpi-anchored-axonal-glycoproteins-in-neural-development-and-neurological-disorders
#4
REVIEW
Gianfranco Gennarini, Antonella Bizzoca, Sabrina Picocci, Daniela Puzzo, Patrizia Corsi, Andrew J W Furley
This review article focuses on the Contactin (CNTN) subset of the Immunoglobulin supergene family (IgC2/FNIII molecules), whose components share structural properties (the association of Immunoglobulin type C2 with Fibronectin type III domains), as well as a general role in cell contact formation and axonal growth control. IgC2/FNIII molecules include 6 highly related components (CNTN 1-6), associated with the cell membrane via a Glycosyl Phosphatidyl Inositol (GPI)-containing lipid tail. Contactin 1 and Contactin 2 share ~50 (49...
November 18, 2016: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/27845167/synapse-organization-and-modulation-via-c1q-family-proteins-and-their-receptors-in-the-central-nervous-system
#5
REVIEW
Keiko Matsuda
Several C1q family members, related to the C1q complement component are highly and predominantly expressed in the central nervous system. Cbln1, which belongs to the Cbln subfamily of C1q proteins, is released from cerebellar granule cells and plays a crucial role in the formation and function of parallel fiber-Purkinje cell synapses. This is achieved by formation of a trans-synaptic tripartite complex which is composed of one unit of the Cbln1 hexamer, monomeric neurexin (NRX) containing a splice site 4 insertion at presynaptic terminals and the postsynaptic GluD2 dimers...
November 11, 2016: Neuroscience Research
https://www.readbyqxmd.com/read/27832597/caveolin-1-regulation-of-disrupted-in-schizophrenia-1-as-a-potential-therapeutic-target-for-schizophrenia
#6
Adam Kassan, Junji Egawa, Zheng Zhang, Angels Almenar-Queralt, Quynh My Nguyen, Yasaman Lajevardi, Kaitlyn Kim, Edmund Posadas, Dilip V Jeste, David M Roth, Piyush M Patel, Hemal H Patel, Brian P Head
BACKGROUND: Schizophrenia is a debilitating psychiatric disorder manifested in early adulthood. Disrupted-In-Schizophrenia-1 (DISC1) is a susceptible gene for schizophrenia (54, 76, 101) implicated in neuronal development, brain maturation and neuroplasticity (12, 20). Therefore, DISC1 is a promising candidate gene for schizophrenia, but the molecular mechanisms underlying its role in the pathogenesis of the disease are still poorly understood. Interestingly, Caveolin-1 (Cav-1), a cholesterol binding and scaffolding protein, regulates neuronal signal transduction and promotes neuroplasticity...
November 2, 2016: Journal of Neurophysiology
https://www.readbyqxmd.com/read/27812179/protein-o-mannosylation-in-the-murine-brain-occurrence-of-mono-o-mannosyl-glycans-and-identification-of-new-substrates
#7
Markus F Bartels, Patrick R Winterhalter, Jin Yu, Yan Liu, Mark Lommel, Frank Möhrlen, Huaiyu Hu, Ten Feizi, Ulrika Westerlind, Thomas Ruppert, Sabine Strahl
Protein O-mannosylation is a post-translational modification essential for correct development of mammals. In humans, deficient O-mannosylation results in severe congenital muscular dystrophies often associated with impaired brain and eye development. Although various O-mannosylated proteins have been identified in the recent years, the distribution of O-mannosyl glycans in the mammalian brain and target proteins are still not well defined. In the present study, rabbit monoclonal antibodies directed against the O-mannosylated peptide YAT(α1-Man)AV were generated...
2016: PloS One
https://www.readbyqxmd.com/read/27810425/role-of-lrrtms-in-synapse-development-and-plasticity
#8
REVIEW
Reiko T Roppongi, Benyamin Karimi, Tabrez J Siddiqui
Leucine-rich-repeat transmembrane neuronal proteins (LRRTMs) are a family of four synapse organizing proteins critical for the development and function of excitatory synapses. The genes encoding LRRTMs and their binding partners, neurexins and HSPGs, are strongly associated with multiple psychiatric disorders. Here, we review the literature covering their structural features, expression patterns in the developing and adult brains, evolutionary origins, and discovery as synaptogenic proteins. We also discuss their role in the development and plasticity of excitatory synapses as well as their disease associations...
October 31, 2016: Neuroscience Research
https://www.readbyqxmd.com/read/27805570/distinct-roles-for-extracellular-and-intracellular-domains-in-neuroligin-function-at-inhibitory-synapses
#9
Quynh-Anh Nguyen, Meryl E Horn, Roger A Nicoll
Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses...
November 2, 2016: ELife
https://www.readbyqxmd.com/read/27725662/developmental-plasticity-shapes-synaptic-phenotypes-of-autism-associated-neuroligin-3-mutations-in-the-calyx-of-held
#10
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
https://www.readbyqxmd.com/read/27717669/the-lgi1-adam22-protein-complex-in-synaptic-transmission-and-synaptic-disorders
#11
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
https://www.readbyqxmd.com/read/27707967/neuronal-dystroglycan-is-necessary-for-formation-and-maintenance-of-functional-cck-positive-basket-cell-terminals-on-pyramidal-cells
#12
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
https://www.readbyqxmd.com/read/27697534/emerging-roles-of-the-neurotrophin-receptor-trkc-in-synapse-organization
#13
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
https://www.readbyqxmd.com/read/27664583/functions-of-synapse-adhesion-molecules-neurexin-neuroligins-and-neurodevelopmental-disorders
#14
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
https://www.readbyqxmd.com/read/27662481/the-snare-protein-syntaxin-3-confers-specificity-for-polarized-axonal-trafficking-in-neurons
#15
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
https://www.readbyqxmd.com/read/27621318/molecular-architecture-of-contactin-associated-protein-like-2-cntnap2-and-its-interaction-with-contactin-2-cntn2
#16
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 multidomain neuronal adhesion molecule implicated in a number of neurological disorders, including epilepsy, schizophrenia, autism spectrum disorder, 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 envelope...
November 11, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27608760/altered-cortical-dynamics-and-cognitive-function-upon-haploinsufficiency-of-the-autism-linked-excitatory-synaptic-suppressor-mdga2
#17
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
https://www.readbyqxmd.com/read/27594578/syncams-from-axon-guidance-to-neurodevelopmental-disorders
#18
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
https://www.readbyqxmd.com/read/27528753/stars-in-the-cns
#19
REVIEW
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
https://www.readbyqxmd.com/read/27418511/structural-basis-for-integration-of-glud-receptors-within-synaptic-organizer-complexes
#20
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
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