Neurexin–Neuroligin Signaling in Synapse Development Ann Marie Craig and Yunhee Kang
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Cellular and Synaptic Network Defects in Autism
Cellular and synaptic network defects in autism The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Peca, Joao, and Guoping Feng. “Cellular and Synaptic Network Defects in Autism.” Current Opinion in Neurobiology 22, no. 5 (October 2012): 866–872. As Published http://dx.doi.org/10.1016/j.conb.2012.02.015 Publisher Elsevier Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/102179 Terms of Use Creative Commons Attribution-Noncommercial-NoDerivatives Detailed Terms http://creativecommons.org/licenses/by-nc-nd/4.0/ NIH Public Access Author Manuscript Curr Opin Neurobiol. Author manuscript; available in PMC 2013 October 01. Published in final edited form as: Curr Opin Neurobiol. 2012 October ; 22(5): 866–872. doi:10.1016/j.conb.2012.02.015. Cellular and synaptic network defects in autism João Peça1 and Guoping Feng1,2 $watermark-text1McGovern $watermark-text Institute $watermark-text for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 2Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA Abstract Many candidate genes are now thought to confer susceptibility to autism spectrum disorder (ASD). Here we review four interrelated complexes, each composed of multiple families of genes that functionally coalesce on common cellular pathways. We illustrate a common thread in the organization of glutamatergic synapses and suggest a link between genes involved in Tuberous Sclerosis Complex, Fragile X syndrome, Angelman syndrome and several synaptic ASD candidate genes. When viewed in this context, progress in deciphering the molecular architecture of cellular protein-protein interactions together with the unraveling of synaptic dysfunction in neural networks may prove pivotal to advancing our understanding of ASDs. -
The Classification of Esterases: an Important Gene Family Involved in Insecticide Resistance - a Review
Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 107(4): 437-449, June 2012 437 The classification of esterases: an important gene family involved in insecticide resistance - A Review Isabela Reis Montella1,2, Renata Schama1,2,3/+, Denise Valle1,2,3 1Laboratório de Fisiologia e Controle de Artrópodes Vetores, Instituto Oswaldo Cruz-Fiocruz, Av. Brasil 4365, 21040-900 Rio de Janeiro, RJ, Brasil 2Instituto de Biologia do Exército, Rio de Janeiro, RJ, Brasil 3Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular, Rio de Janeiro, RJ, Brasil The use of chemical insecticides continues to play a major role in the control of disease vector populations, which is leading to the global dissemination of insecticide resistance. A greater capacity to detoxify insecticides, due to an increase in the expression or activity of three major enzyme families, also known as metabolic resistance, is one major resistance mechanisms. The esterase family of enzymes hydrolyse ester bonds, which are present in a wide range of insecticides; therefore, these enzymes may be involved in resistance to the main chemicals employed in control programs. Historically, insecticide resistance has driven research on insect esterases and schemes for their classification. Currently, several different nomenclatures are used to describe the esterases of distinct species and a universal standard classification does not exist. The esterase gene family appears to be rapidly evolving and each insect species has a unique complement of detoxification genes with only a few orthologues across species. The examples listed in this review cover different aspects of their biochemical nature. However, they do not appear to contribute to reliably distinguish among the different resistance mechanisms. -
Interaction of Acetylcholinesterase with Neurexin-1Β Regulates
Xiang et al. Molecular Brain 2014, 7:15 http://www.molecularbrain.com/content/7/1/15 RESEARCH Open Access Interaction of Acetylcholinesterase with Neurexin-1β regulates Glutamatergic Synaptic stability in Hippocampal neurons Yun-Yan Xiang1,2†, Haiheng Dong3†, Burton B Yang4, John F MacDonald1,2 and Wei-Yang Lu1,2,3,5* Abstract Background: Excess expression of acetylcholinesterase (AChE) in the cortex and hippocampus causes a decrease in the number of glutamatergic synapses and alters the expression of neurexin and neuroligin, trans-synaptic proteins that control synaptic stability. The molecular sequence and three-dimensional structure of AChE are homologous to the corresponding aspects of the ectodomain of neuroligin. This study investigated whether excess AChE interacts physically with neurexin to destabilize glutamatergic synapses. Results: The results showed that AChE clusters colocalized with neurexin assemblies in the neurites of hippocampal neurons and that AChE co-immunoprecipitated with neurexin from the lysate of these neurons. Moreover, when expressed in human embryonic kidney 293 cells, N-glycosylated AChE co-immunoprecipitated with non-O–glycosylated neurexin-1β,withN-glycosylation of the AChE being required for this co-precipitation to occur. Increasing extracellular AChE decreased the association of neurexin with neuroligin and inhibited neuroligin-induced synaptogenesis. The number and activity of excitatory synapses in cultured hippocampal neurons were reduced by extracellular catalytically inactive AChE. Conclusions: Excessive glycosylated AChE could competitively disrupt a subset of the neurexin–neuroligin junctions consequently impairing the integrity of glutamatergic synapses. This might serve a molecular mechanism of excessive AChE induced neurodegeneration. Keywords: Protein interaction, Glycosylation, Neurodegeneration, Synaptic apoptosis Introduction globular monomers and dimers of AChE-S. -
Lrrtms and Neuroligins Bind Neurexins with a Differential Code to Cooperate in Glutamate Synapse Development
The Journal of Neuroscience, June 2, 2010 • 30(22):7495–7506 • 7495 Cellular/Molecular LRRTMs and Neuroligins Bind Neurexins with a Differential Code to Cooperate in Glutamate Synapse Development Tabrez J. Siddiqui, Raika Pancaroglu, Yunhee Kang, Amanda Rooyakkers, and Ann Marie Craig Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) were recently found to instruct presynaptic and mediate postsynaptic glutamatergic differentiation. In a candidate screen, here we identify neurexin-1 lacking an insert at splice site 4 (ϪS4) as a ligand for LRRTM2. Neurexins bind LRRTM2 with a similar affinity but distinct code from the code for binding neuroligin-1 (the predominant form of neuroligin-1 at glutamate synapses, containing the B splice site insert). Whereas neuroligin-1 binds to neurexins 1, 2, and 3  but not ␣ variants, regardless of insert at splice site 4, LRRTM2 binds to neurexins 1, 2, and 3 ␣ and  variants specifically lacking an insert at splicesite4.WefurthershowthatthisbindingcodeisconservedinLRRTM1,thefamilymemberlinkedtoschizophreniaandhandedness, and that the code is functional in a coculture hemisynapse formation assay. Mutagenesis of LRRTM2 to prevent binding to neurexins abolishes presynaptic inducing activity of LRRTM2. Remarkably, mutagenesis of neurexins shows that the binding face on neurexin-1 (ϪS4) is highly overlapping for the structurally distinct LRRTM2 and neuroligin-1 partners. Finally, we explore here the interplay of neuroligin-1 and LRRTM2 in synapse regulation. In neuron cultures, LRRTM2 is more potent than neuroligin-1 in promoting synaptic differentiation, and, most importantly, these two families of neurexin-binding partners cooperate in an additive or synergistic manner. -
Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies
International Journal of Environmental Research and Public Health Review Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies Noor B. Almandil 1,† , Deem N. Alkuroud 2,†, Sayed AbdulAzeez 2, Abdulla AlSulaiman 3, Abdelhamid Elaissari 4 and J. Francis Borgio 2,* 1 Department of Clinical Pharmacy Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] 2 Department of Genetic Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] (D.N.A.); [email protected] (S.A.) 3 Department of Neurology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] or [email protected] 4 Univ Lyon, University Claude Bernard Lyon-1, CNRS, LAGEP-UMR 5007, F-69622 Lyon, France; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +966-13-333-0864 † These authors contributed equally to this work. Received: 26 January 2019; Accepted: 19 February 2019; Published: 23 February 2019 Abstract: One of the most common neurodevelopmental disorders worldwide is autism spectrum disorder (ASD), which is characterized by language delay, impaired communication interactions, and repetitive patterns of behavior caused by environmental and genetic factors. This review aims to provide a comprehensive survey of recently published literature on ASD and especially novel insights into excitatory synaptic transmission. Even though numerous genes have been discovered that play roles in ASD, a good understanding of the pathophysiologic process of ASD is still lacking. -
Slitrks Control Excitatory and Inhibitory Synapse Formation with LAR
Slitrks control excitatory and inhibitory synapse SEE COMMENTARY formation with LAR receptor protein tyrosine phosphatases Yeong Shin Yima,1, Younghee Kwonb,1, Jungyong Namc, Hong In Yoona, Kangduk Leeb, Dong Goo Kima, Eunjoon Kimc, Chul Hoon Kima,2, and Jaewon Kob,2 aDepartment of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea; bDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; and cCenter for Synaptic Brain Dysfunctions, Institute for Basic Science, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved December 26, 2012 (received for review June 11, 2012) The balance between excitatory and inhibitory synaptic inputs, share a similar domain organization comprising three Ig domains which is governed by multiple synapse organizers, controls neural and four to eight fibronectin type III repeats. LAR-RPTP family circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are members are evolutionarily conserved and are functionally required a family of synapse organizers, whose emerging synaptic roles are for axon guidance and synapse formation (15). Recent studies have incompletely understood. Here, we report that Slitrks are enriched shown that netrin-G ligand-3 (NGL-3), neurotrophin receptor ty- in postsynaptic densities in rat brains. Overexpression of Slitrks rosine kinase C (TrkC), and IL-1 receptor accessory protein-like 1 promoted synapse formation, whereas RNAi-mediated knock- (IL1RAPL1) bind to all three LAR-RPTP family members or dis- down of Slitrks decreased synapse density. -
Deletion of Α-Neurexin II Results in Autism-Related
OPEN Citation: Transl Psychiatry (2014) 4, e484; doi:10.1038/tp.2014.123 www.nature.com/tp ORIGINAL ARTICLE Deletion of α-neurexin II results in autism-related behaviors in mice J Dachtler1, J Glasper2, RN Cohen1, JL Ivorra1, DJ Swiffen1, AJ Jackson1, MK Harte2, RJ Rodgers3 and SJ Clapcote1 Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein α-neurexin II (Nrxn2α), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed Nrxn2α knockout (KO) mice that genetically model Nrxn2α deficiency in vivo. We report that Nrxn2α KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2α KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2α KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1, was significantly decreased in the hippocampus of Nrxn2α KO mice, which is suggestive of deficiencies in presynaptic vesicular release. -
Acetylcholinesterase — New Roles for Gate a Relatively Long Distance to Reach the Active Site, Ache Is One of the Fastest an Old Actor Enzymes14
PERSPECTIVES be answered regarding AChE catalysis; for OPINION example, the mechanism behind the extremely fast turnover rate of the enzyme. Despite the fact that the substrate has to navi- Acetylcholinesterase — new roles for gate a relatively long distance to reach the active site, AChE is one of the fastest an old actor enzymes14. One theory to explain this phe- nomenon has to do with the unusually strong electric field of AChE. It has been argued that Hermona Soreq and Shlomo Seidman this field assists catalysis by attracting the cationic substrate and expelling the anionic The discovery of the first neurotransmitter — understanding of AChE functions beyond the acetate product15. Site-directed mutagenesis, acetylcholine — was soon followed by the classical view and suggest the molecular basis however, has indicated that reducing the elec- discovery of its hydrolysing enzyme, for its functional heterogeneity. tric field has no effect on catalysis16.However, acetylcholinesterase. The role of the same approach has indicated an effect on acetylcholinesterase in terminating From early to recent discoveries the rate of association of fasciculin, a peptide acetylcholine-mediated neurotransmission The unique biochemical properties and phys- that can inhibit AChE17. made it the focus of intense research for iological significance of AChE make it an much of the past century. But the complexity interesting target for detailed structure–func- of acetylcholinesterase gene regulation and tion analysis. AChE-coding sequences have recent evidence for some of the long- been cloned so far from a range of evolution- a Peripheral Choline binding site suspected ‘non-classical’ actions of this arily diverse vertebrate and invertebrate binding enzyme have more recently driven a species that include insects, nematodes, fish, site profound revolution in acetylcholinesterase reptiles, birds and several mammals, among Active site research. -
Art of Music, As Harmony of the Spheres and Autism Spectrum Disorder
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 6 September 2016 doi:10.20944/preprints201609.0022.v1 Review Art of Music, as Harmony of the Spheres and Autism Spectrum Disorder Bharathi Geetha *, Thangaraj Sugunadevi, Babu Srija, Nagarajan Laleethambika and Vellingiri Balachandar * Human Molecular Genetics and Stem Cell Laboratory, Department of Human Genetics & Molecular Biology, Bharathiar University, Coimbatore, 641046 Tamil Nadu, India; [email protected] (T.S.); [email protected] (B.S.); [email protected] (N.L.) * Correspondence: [email protected] (B.G.); [email protected] or [email protected] (V.B.); Tel.: +91-814-405-2274 (B.G.); +91-422-242-2514 (V.B.); Fax: +91-422-242-2387 (V.B.) Abstract: Music has the innate potential to reach all parts of the brain, stimulates certain brain areas which are not achievable through other modalities. Music Therapy (MT) is being used for more than a century to treat individuals who needs personalized care. MT optimizes motor, speech and language responsibilities of the brain and improves cognitive performance. Pervasive developmentdisorder (PDD) is a multifaceted, neuro developmental disorder and autism spectrum disorder (ASD) comes under PDD, which is defined by deficiencies in three principal spheres: social connection with others, communicative and normal movement skills. The conventional imaging studies illustrate reduced brain area connectivity in people with ASD, involving selected parts of the brain cortex. People with ASD express much interest in musical activities which engages the brain network areas and improves communication and social skills.The main objective of this review is to analyze the potential role of MT in treating the neurological conditions, particularly ASD. -
Mouse Neurexin-1 Deletion Causes Correlated Electrophysiological And
Mouse neurexin-1␣ deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments Mark R. Ethertona,1, Cory A. Blaissb,1, Craig M. Powellb,c, and Thomas C. Su¨ dhof a,d,e,f,g,2 aDepartment of Molecular and Cellular Physiology and dHoward Hughes Medical Institute, Stanford University, 1050 Arastradero Road, CA 94304; and Departments of bNeurology, cPsychiatry, eNeuroscience, and fMolecular Genetics, and gHoward Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 Contributed by Thomas C. Su¨dhof, September 9, 2009 (sent for review August 2, 2009) Deletions in the neurexin-1␣ gene were identified in large-scale patients carry neurexin-1␣ deletions. Thus, understanding the unbiased screens for copy-number variations in patients with biology of neurexin-1␣ and its role in the pathogenesis of ASDs autism or schizophrenia. To explore the underlying biology, we and schizophrenia assumes added importance. In view of the studied the electrophysiological and behavioral phenotype of mice human clinical genetics data, we have now performed an lacking neurexin-1␣. Hippocampal slice physiology uncovered a in-depth analysis of the synaptic phenotype produced by the defect in excitatory synaptic strength in neurexin-1␣ deficient neurexin-1␣ deletion in mice, and examined the behavioral mice, as revealed by a decrease in miniature excitatory postsyn- consequences of this deletion. Based on the viability of aptic current (EPSC) frequency and in the input-output relation of neurexin-1␣ KO mice and on the human condition, we ex- evoked postsynaptic potentials. This defect was specific for exci- pected a limited phenotype without incapacitating impair- tatory synaptic transmission, because no change in inhibitory ments. -
Neuroligin 3 (Nlgn3) Knockout Rat
Genetically engineered models (GEMS) Neuroligin 3 (Nlgn3) knockout rat Model Neuroligin 3 (Nlgn3) knockout rat Strain HsdSage:SD- Nlgn3tm1sage Location U.S. Availability Cryopreserved Characteristics/husbandry Research use + This model was created in collaboration with Autism Speaks + Autism and is currently undergoing phenotypic characterization by + Asperger’s syndrome Dr. Richard Paylor at Baylor College of Medicine + Synaptic plasticity + Preliminary results suggest that Nlgn3 knockout rats are less anxious and exhibit decreased juvenile play, deficits in Origin sensorimotor gating and increased perseverative behaviors The Neuroligin 3 (Nlgn3) KO rat model was originally created + Homozygous knockout rats exhibit complete loss of target at SAGE Labs, Inc. in St. Louis, MO and distributed out of the protein as demonstrated by Western blot Boyertown, PA facility. The line continues to be maintained through the original SAGE Labs animal inventory acquired by + Mutations in Nlgn3 have been associated with autism and Asperger’s syndrome Envigo. + Nlgn3 is a member of the broader neuroligins, neuronal cell surface proteins thought to play a role in synaptic plasticity Description This model contains a biallelic deletion of the neuroligin 3 gene + Background strain: Sprague Dawley (Nlgn3). Mutations in Nlgn3 have been linked with autism and Asperger’s syndrome. This model is useful for understanding Zygosity genotype the role of neuroligins in the development of autism spectrum disorders. + Cryopreserved as heterozygous embryos Neuroligins -
The Untold Stories of the Speech Gene, the FOXP2 Cancer Gene
www.Genes&Cancer.com Genes & Cancer, Vol. 9 (1-2), January 2018 The untold stories of the speech gene, the FOXP2 cancer gene Maria Jesus Herrero1,* and Yorick Gitton2,* 1 Center for Neuroscience Research, Children’s National Medical Center, NW, Washington, DC, USA 2 Sorbonne University, INSERM, CNRS, Vision Institute Research Center, Paris, France * Both authors contributed equally to this work Correspondence to: Yorick Gitton, email: [email protected] Keywords: FOXP2 factor, oncogene, cancer, prognosis, language Received: March 01, 2018 Accepted: April 02, 2018 Published: April 18, 2018 Copyright: Herrero and Gitton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT FOXP2 encodes a transcription factor involved in speech and language acquisition. Growing evidence now suggests that dysregulated FOXP2 activity may also be instrumental in human oncogenesis, along the lines of other cardinal developmental transcription factors such as DLX5 and DLX6 [1–4]. Several FOXP family members are directly involved during cancer initiation, maintenance and progression in the adult [5–8]. This may comprise either a pro- oncogenic activity or a deficient tumor-suppressor role, depending upon cell types and associated signaling pathways. While FOXP2 is expressed in numerous cell types, its expression has been found to be down-regulated in breast cancer [9], hepatocellular carcinoma [8] and gastric cancer biopsies [10]. Conversely, overexpressed FOXP2 has been reported in multiple myelomas, MGUS (Monoclonal Gammopathy of Undetermined Significance), several subtypes of lymphomas [5,11], as well as in neuroblastomas [12] and ERG fusion-negative prostate cancers [13].