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María Lázaro-Peña, Carlos Díaz-Balzac, Hannes Bülow, Scott Emmons
The nervous system regulates complex behaviors through a network of neurons interconnected by synapses. How specific synaptic connections are genetically determined is still unclear. Male mating is the most complex behavior in C. elegans It is composed of sequential steps that are governed by more than 3,000 chemical connections. Here we show that heparan sulfates (HS) play a role in the formation and function of the male neural network. HS, sulfated in position 3 by the HS modification enzyme HST-3.1 / HS 3- O -sulfotransferase and attached to the HSPG glypicans LON-2/glypican and GPN-1/glypican, functions cell-autonomously and non-autonomously for response to hermaphrodite contact during mating...
March 20, 2018: Genetics
Guanglin Xing, Moyi Li, Yichen Sun, Menglong Rui, Yan Zhuang, Huihui Lv, Junhai Han, Zhengping Jia, Wei Xie
Neuroligins are postsynaptic adhesion molecules that are essential for postsynaptic specialization and synaptic function. But the underlying molecular mechanisms of Neuroligin functions remain unclear. We found that Drosophila Neuroligin1 (DNlg1) regulates synaptic structure and function through WAVE regulatory complex (WRC)-mediated postsynaptic actin reorganization. The disruption of DNlg1, DNlg2, or their presynaptic partner Neurexin (DNrx) led to a dramatic decrease in the amount of F-actin. Further study showed that DNlg1, but not DNlg2 or DNlg3, directly interacts with the WRC via its C-terminal interacting receptor sequence...
March 14, 2018: ELife
Zhifeng Wang, Zhouqing Chen, Junjie Yang, Ziying Yang, Jia Yin, Xiaochun Duan, Haitao Shen, Haiying Li, Zhong Wang, Gang Chen
Postsynaptic density protein-95 (PSD95) plays important roles in the formation, differentiation, remodeling, and maturation of neuronal synapses. This study is to estimate the potential role of PSD95 in cognitive dysfunction and synaptic injury following intracerebral hemorrhage (ICH). The interaction between PSD95 and NMDA receptor subunit NR2B-neurotransmitter nitric oxide synthase (nNOS) could form a signal protein complex mediating excitatory signaling. Besides NR2B-nNOS, PSD95 also can bind to neurexin-1-neuroligin-1 to form a complex and participates in maintaining synaptic function...
January 1, 2018: Journal of Cerebral Blood Flow and Metabolism
William D Constance, Amrita Mukherjee, Yvette E Fisher, Sinziana Pop, Eric Blanc, Yusuke Toyama, Darren W Williams
Building arborisations of the right size and shape is fundamental for neural network function. Live imaging in vertebrate brains strongly suggests that nascent synapses are critical for branch growth during development. The molecular mechanisms underlying this are largely unknown. Here we present a novel system in Drosophila for studying the development of complex arborisations live, in vivo during metamorphosis. In growing arborisations we see branch dynamics and localisations of presynaptic proteins very similar to the 'synaptotropic growth' described in fish/frogs...
March 5, 2018: ELife
Juan P Grosso, Jesica A Barneto, Rodrigo A Velarde, Eduardo A Pagano, Jorge A Zavala, Walter M Farina
The effect of early experiences on the brain during a sensitive period exerts a long-lasting influence on the mature individual. Despite behavioral and neural plasticity caused by early experiences having been reported in the honeybee Apis mellifera , the presence of a sensitive period in which associative experiences lead to pronounced modifications in the adult nervous system is still unclear. Laboratory-reared bees were fed with scented food within specific temporal windows and were assessed for memory retention, in the regulation of gene expression related to the synaptic formation and in the olfactory perception of their antennae at 17 days of age...
2018: Frontiers in Behavioral Neuroscience
Leslie E W LaConte, Vrushali Chavan, Abdallah F Elias, Cynthia Hudson, Corbin Schwanke, Katie Styren, Jonathan Shoof, Fernando Kok, Sarika Srivastava, Konark Mukherjee
Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia...
February 9, 2018: Human Genetics
Kathryn A Schiel
This etiologic model proposes that Alzheimers Disease (AD) arises when an unusually rapid increase in ventricle volume triggers axon stretch that culminates in the physical separation of trans-synaptic proteins. As a result, these proteins, such as neurexin, neuroligin, N-Cadherin and Amyloid Precursor Protein (APP), experience a change in the configuration of their cytoplasmic tail, so that instead of transmitting signals to create and maintain synaptic structure they activate enzymes, and generate molecules, that stimulate neurite growth; for example, the transformation of the N-Cadherin tail dissolves its complex with presenilin and β-catenin triggering activation of glycogen synthase kinase 3 beta (GSK3β) and cytoskeletal disruption...
February 2018: Medical Hypotheses
Flora H Duits, Gunnar Brinkmalm, Charlotte E Teunissen, Ann Brinkmalm, Philip Scheltens, Wiesje M Van der Flier, Henrik Zetterberg, Kaj Blennow
BACKGROUND: We investigated whether a panel of 12 potential novel biomarkers consisting of proteins involved in synapse functioning and immunity would be able to distinguish patients with Alzheimer's disease (AD) and patients with mild cognitive impairment (MCI) from control subjects. METHODS: We included 40 control subjects, 40 subjects with MCI, and 40 subjects with AD from the Amsterdam Dementia Cohort who were matched for age and sex (age 65 ± 5 years, 19 [48%] women)...
January 15, 2018: Alzheimer's Research & Therapy
Michael P Hart, Oliver Hobert
During development and adulthood, brain plasticity is evident at several levels, from synaptic structure and function to the outgrowth of dendrites and axons. Whether and how sex impinges on neuronal plasticity is poorly understood. Here we show that the sex-shared GABA (γ-aminobutyric acid)-releasing DVB neuron in Caenorhabditis elegans displays experience-dependent and sexually dimorphic morphological plasticity, characterized by the stochastic and dynamic addition of multiple neurites in adult males. These added neurites enable synaptic rewiring of the DVB neuron and instruct a functional switch of the neuron that directly modifies a step of male mating behaviour...
January 10, 2018: Nature
Steven A Connor, Ina Ammendrup-Johnsen, Yasushi Kishimoto, Parisa Karimi Tari, Vedrana Cvetkovska, Takashi Harada, Daiki Ojima, Tohru Yamamoto, Yu Tian Wang, Ann Marie Craig
Synaptopathies contributing to neurodevelopmental disorders are linked to mutations in synaptic organizing molecules, including postsynaptic neuroligins, presynaptic neurexins, and MDGAs, which regulate their interaction. The role of MDGA1 in suppressing inhibitory versus excitatory synapses is controversial based on in vitro studies. We show that genetic deletion of MDGA1 in vivo elevates hippocampal CA1 inhibitory, but not excitatory, synapse density and transmission. Furthermore, MDGA1 is selectively expressed by pyramidal neurons and regulates perisomatic, but not distal dendritic, inhibitory synapses...
December 26, 2017: Cell Reports
Emilia Servián-Morilla, Estefanía Robles-Lanuza, Ana C Sánchez-Hidalgo, Rafael J Camacho-Garcia, Juan A Paez-Gomez, Fabiola Mavillard, Carlos A Saura, Amalia Martinez-Mir, Francisco G Scholl
Proteolytic processing of synaptic adhesion components can accommodate the function of synapses to activity-dependent changes. The adhesion system formed by neurexins (Nrxns) and neuroligins (Nlgns) bidirectionally orchestrate the function of presynaptic and postsynaptic terminals. Previous studies have shown that presenilins (PS), components of the gamma-secretase complex frequently mutated in familial Alzheimer's disease, clear from glutamatergic terminals the accumulation of Nrxn C-terminal fragments (Nrxn-CTF) generated by ectodomain shedding...
January 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Enas Kasem, Taiga Kurihara, Katsuhiko Tabuchi
Neurexins are a family of presynaptic single-pass transmembrane proteins that act as synaptic organizers in mammals. The neurexins consist of three genes (NRXN1, NRXN2, and NRXN3), each of which produces a longer α- and shorter β-form. Genomic alterations in NRXN genes have been identified in a wide variety of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia, intellectual disability (ID), and addiction. Remarkably, a bi-allelic deficiency of NRXN1 was recently linked to Pitt-Hopkins syndrome...
February 2018: Neuroscience Research
Michael A Spinner, David A Walla, Tory G Herman
Syd-1 proteins are required for presynaptic development in worm, fly, and mouse. Syd-1 proteins in all three species contain a Rho GTPase activating protein (GAP)-like domain of unclear significance: invertebrate Syd-1s are thought to lack GAP activity, and mouse mSYD1A has GAP activity that is thought to be dispensable for its function. Here, we show that Drosophila melanogaster Syd-1 can interact with all six fly Rhos and has GAP activity toward Rac1 and Cdc42. During development, fly Syd-1 clusters multiple presynaptic proteins at the neuromuscular junction (NMJ), including the cell adhesion molecule Neurexin (Nrx-1) and the active zone (AZ) component Bruchpilot (Brp), both of which Syd-1 binds directly...
February 2018: Genetics
Hongwei Tu, Tao Peng, Jiaxian Liu, Xiaohui Chen, Chengji Fan, Zhibin Huang, Yiyue Zhang, Fei Zou, Xiaojing Meng
Low-dose chronic lead (Pb) exposure interferes with the development of the nervous system, which may lead to learning disabilities, behavioral abnormalities, and mental retardation. Neurexins (Nrxns) are synaptic cell-adhesion molecules associated with neurological disorders. We hypothesized that Pb can affect the expression of nrxns during synapse formation and alter the phenotype behavior. Here, apoptosis, nrxns mRNA expression, and alterations of locomotion were examined after exposure to Pb in zebrafish embryos/larvae...
January 2018: Aquatic Toxicology
Michisuke Yuzaki
Research in the last two decades has identified many synaptic organizers in the central nervous system that directly regulate the assembly of preand/ or postsynaptic molecules, such as synaptic vesicles, active zone proteins, and neurotransmitter receptors. They are classified into secreted factors and cell adhesion molecules, such as neurexins and neuroligins. Certain secreted factors are termed extracellular scaffolding proteins (ESPs) because they are components of the synaptic extracellular matrix and serve as a scaffold at the synaptic cleft...
November 20, 2017: Annual Review of Physiology
C Fabbri, K E Tansey, R H Perlis, J Hauser, N Henigsberg, W Maier, O Mors, A Placentino, M Rietschel, D Souery, G Breen, C Curtis, L Sang-Hyuk, S Newhouse, H Patel, M Guipponi, N Perroud, G Bondolfi, M O'Donovan, G Lewis, J M Biernacka, R M Weinshilboum, A Farmer, K J Aitchison, I Craig, P McGuffin, R Uher, C M Lewis
Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation...
November 21, 2017: Pharmacogenomics Journal
Jeff A Stogsdill, Juan Ramirez, Di Liu, Yong Ho Kim, Katherine T Baldwin, Eray Enustun, Tiffany Ejikeme, Ru-Rong Ji, Cagla Eroglu
Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins...
November 8, 2017: Nature
Thomas C Südhof
Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here, we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits...
November 2, 2017: Cell
Himani Pandey, Katia Bourahmoune, Takato Honda, Ken Honjo, Kazuki Kurita, Tomohito Sato, Akira Sawa, Katsuo Furukubo-Tokunaga
Originally identified at the breakpoint of a (1;11)(q42.1; q14.3) chromosomal translocation in a Scottish family with a wide range of mental disorders, the DISC1 gene has been a focus of intensive investigations as an entry point to study the molecular mechanisms of diverse mental dysfunctions. Perturbations of the DISC1 functions lead to behavioral changes in animal models, which are relevant to psychiatric conditions in patients. In this work, we have expressed the human DISC1 gene in the fruit fly (Drosophila melanogaster) and performed a genetic screening for the mutations of psychiatric risk genes that cause modifications of DISC1 synaptic phenotypes at the neuromuscular junction...
October 27, 2017: NPJ Schizophrenia
Jia Wang, Jianhua Gong, Li Li, Yanlin Chen, Lingfei Liu, HuaiTing Gu, Xiu Luo, Fang Hou, Jiajia Zhang, Ranran Song
Increasing evidence suggests that abnormal synaptic function leads to neuronal developmental disorders and is an important component of the etiology of autism spectrum disorder (ASD). Neurexins are presynaptic cell-adhesion molecules that affect the function of synapses and mediate the conduction of nerve signals. Thus, neurexins are attractive candidate genes for autism. Since gene families have greater power to reveal genetic association than single genes, we designed this case-control study to investigate six genetic variants in three neurexin genes (NRXN1, NRXN2, and NRXN3) in a Chinese population including 529 ASD patients and 1,923 healthy controls...
October 16, 2017: Autism Research: Official Journal of the International Society for Autism Research
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