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Pranay Srivastava, Yogesh K Dhuriya, Vivek Kumar, Akriti Srivastava, Richa Gupta, Rajendra K Shukla, Rajesh S Yadav, Hari N Dwivedi, Aditya B Pant, Vinay K Khanna
Protective efficacy of curcumin in arsenic induced NMDA receptor dysfunctions and PI3 K/Akt/ GSK3β signalling in hippocampus has been investigated in vivo and in vitro. Exposure to sodium arsenite (in vivo - 20 mg/kg, body weight p.o. for 28 days; in vitro - 10 µM for 24 hrs) and curcumin (in vivo - 100 mg/kg body weight p.o. for 28 days; in vitro - 20 µM for 24 hrs) was carried out alone or simultaneously. Treatment with curcumin ameliorated sodium arsenite induced alterations in the levels of NMDA receptors, its receptor subunits and synaptic proteins - pCaMKIIα, PSD-95 and SynGAP both in vivo and in vitro...
April 30, 2018: Neurotoxicology
Faye McLeod, Alessandro Bossio, Aude Marzo, Lorenza Ciani, Sara Sibilla, Saad Hannan, Gemma A Wilson, Ernest Palomer, Trevor G Smart, Alasdair Gibb, Patricia C Salinas
The structural and functional plasticity of synapses is critical for learning and memory. Long-term potentiation (LTP) induction promotes spine growth and AMPAR accumulation at excitatory synapses, leading to increased synaptic strength. Glutamate initiates these processes, but the contribution from extracellular modulators is not fully established. Wnts are required for spine formation; however, their impact on activity-mediated spine plasticity and AMPAR localization is unknown. We found that LTP induction rapidly increased synaptic Wnt7a/b protein levels...
April 24, 2018: Cell Reports
Zachary M Grinspan, Niu Tian, Elissa G Yozawitz, Patricia E McGoldrick, Steven M Wolf, Tiffani L McDonough, Aaron Nelson, Baria Hafeez, Stephen B Johnson, Dale C Hesdorffer
Identifying individuals with rare epilepsy syndromes in electronic data sources is difficult, in part because of missing codes in the International Classification of Diseases (ICD) system. Our objectives were the following: (1) to describe the representation of rare epilepsies in other medical vocabularies, to identify gaps; and (2) to compile synonyms and associated terms for rare epilepsies, to facilitate text and natural language processing tools for cohort identification and population-based surveillance...
March 2018: Epilepsia Open
Solveigh Cornelia Koeberle, Shinji Tanaka, Toshihiko Kuriu, Hirohide Iwasaki, Andreas Koeberle, Alexander Schulz, Dario-Lucas Helbing, Yoko Yamagata, Helen Morrison, Shigeo Okabe
The roles of calcium-calmodulin-dependent protein kinase II-alpha (CaMKIIα) in the expression of long-term synaptic plasticity in the adult brain have been extensively studied. However, how increased CaMKIIα activity controls the maturation of neuronal circuits remains incompletely understood. Herein, we show that pyramidal neurons without CaMKIIα activity upregulate the rate of spine addition, resulting in elevated spine density. Genetic elimination of CaMKIIα activity specifically eliminated the observed maturation-dependent suppression of spine formation...
October 17, 2017: Scientific Reports
Satoshi Yokoi, Tsuyoshi Udagawa, Yusuke Fujioka, Daiyu Honda, Haruo Okado, Hirohisa Watanabe, Masahisa Katsuno, Shinsuke Ishigaki, Gen Sobue
FUS is an RNA-binding protein associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated intrinsic roles of FUS in synaptic function. However, the mechanism underlying FUS's regulation of synaptic morphology has remained unclear. We found that reduced mature spines after FUS depletion were associated with the internalization of PSD-95 within the dendritic shaft. Mass spectrometry of PSD-95-interacting proteins identified SynGAP, whose expression decreased after FUS depletion...
September 26, 2017: Cell Reports
Menglong Zeng, Guanhua Bai, Mingjie Zhang
SynGAP, encoded by SYNGAP1, is a Ras/Rap GTPase activator specifically expressed in the nervous systems. SynGAP is one of the most abundant proteins in the postsynaptic densities (PSDs) of excitatory synapses and acts as a critical synaptic activity brake by tuning down synaptic GTPase activities. Mutations of SYNGAP1 have been frequently linked to brain disorders including intellectual disability, autisms, and seizure. SynGAP has been shown to undergo fast dispersions from synapses in response to stimulations, a strategy that neurons use to control the specific activities of the enzyme within the tiny, semi-open compartments in dendritic spines...
May 19, 2017: Small GTPases
Yogesh K Dhuriya, Pranay Srivastava, Rajendra K Shukla, Richa Gupta, Dhirendra Singh, Devendra Parmar, Aditya B Pant, Vinay K Khanna
Effect of prenatal exposure to lambda-cyhalothrin (LCT) has been assessed on the integrity of NMDA receptors and associated post-synaptic signalling in hippocampus of developing rats. Decrease in the binding of [3H]-MK 801, known to label NMDA receptors was observed in hippocampus of rats prenatally exposed to LCT (1 and 3mg/kg body weight) on PD22, compared to controls. Consistent with this, decrease in the mRNA and protein expression of NR1 and NR2B subunits of NMDA receptors was evident in rats prenatally exposed to LCT (1 and 3mg/kg body weight) on PD22...
September 2017: Neurotoxicology
Chae-Seok Lim, Xi Kang, Vincent Mirabella, Huaye Zhang, Qian Bu, Yoichi Araki, Elizabeth T Hoang, Shiqiang Wang, Ying Shen, Sukwoo Choi, Bong-Kiun Kaang, Qiang Chang, Zhiping P Pang, Richard L Huganir, J Julius Zhu
Rapid advances in genetics are linking mutations on genes to diseases at an exponential rate, yet characterizing the gene-mutation-cell-behavior relationships essential for precision medicine remains a daunting task. More than 350 mutations on small GTPase BRaf are associated with various tumors, and ∼40 mutations are associated with the neurodevelopmental disorder cardio-facio-cutaneous syndrome (CFC). We developed a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and ∼50 disease-linked BRaf mutants, including all CFC-linked mutants...
March 15, 2017: Genes & Development
Ward G Walkup, Tara L Mastro, Leslie T Schenker, Jost Vielmetter, Rebecca Hu, Ariella Iancu, Meera Reghunathan, Barry Dylan Bannon, Mary B Kennedy
No abstract text is available yet for this article.
October 19, 2016: ELife
Ward G Walkup, Tara L Mastro, Leslie T Schenker, Jost Vielmetter, Rebecca Hu, Ariella Iancu, Meera Reghunathan, Barry Dylan Bannon, Mary B Kennedy
SynGAP is a Ras/Rap GTPase-activating protein (GAP) that is a major constituent of postsynaptic densities (PSDs) from mammalian forebrain. Its α1 isoform binds to all three PDZ (PSD-95, Discs-large, ZO-1) domains of PSD-95, the principal PSD scaffold, and can occupy as many as 15% of these PDZ domains. We present evidence that synGAP-α1 regulates the composition of the PSD by restricting binding to the PDZ domains of PSD-95. We show that phosphorylation by Ca2+ /calmodulin-dependent protein kinase II (CaMKII) and Polo-like kinase-2 (PLK2) decreases its affinity for the PDZ domains by several fold, which would free PDZ domains for occupancy by other proteins...
September 13, 2016: ELife
Menglong Zeng, Yuan Shang, Yoichi Araki, Tingfeng Guo, Richard L Huganir, Mingjie Zhang
Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange their components with bulk aqueous cytoplasm in synaptic spines. Formation and activity-dependent modulation of PSDs is considered as one of the most basic molecular events governing synaptic plasticity in the nervous system. In this study, we discover that SynGAP, one of the most abundant PSD proteins and a Ras/Rap GTPase activator, forms a homo-trimer and binds to multiple copies of PSD-95...
August 25, 2016: Cell
Jingrui Xing, Hiroki Kimura, Chenyao Wang, Kanako Ishizuka, Itaru Kushima, Yuko Arioka, Akira Yoshimi, Yukako Nakamura, Tomoko Shiino, Tomoko Oya-Ito, Yuto Takasaki, Yota Uno, Takashi Okada, Tetsuya Iidaka, Branko Aleksic, Daisuke Mori, Norio Ozaki
PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible...
2016: Scientific Reports
Maria del Mar Masdeu, Beatriz G Armendáriz, Eduardo Soriano, Jesús Mariano Ureña, Ferran Burgaya
The regulation of focal adhesion kinase (FAK) involves phosphorylation and multiple interactions with other signaling proteins. Some of these pathways are relevant for nervous system functions such as branching, axonal guidance, and plasticity. In this study, we screened mouse brain to identify FAK-interactive proteins and phosphorylatable residues as a first step to address the neuronal functions of this kinase. Using mass spectrometry analysis, we identified new phosphorylated sites (Thr 952, Thr 1048, and Ser 1049), which lie in the FAT domain; and putative new partners for FAK, which include cytoskeletal proteins such as drebrin and MAP 6, adhesion regulators such as neurabin-2 and plakophilin 1, and synapse-associated proteins such as SynGAP and a NMDA receptor subunit...
July 2016: Biochimica et Biophysica Acta
Rong Rong, Hui Yang, Liangqun Rong, Xiue Wei, Qingjie Li, Xiaomei Liu, Hong Gao, Yun Xu, Qingxiu Zhang
Postsynaptic density protein-93 (PSD-93) is enriched in the postsynaptic density and is involved in N-methyl-d-aspartate receptor (NMDAR) triggered neurotoxicity through PSD-93/NMDAR/nNOS signaling pathway. In the present study, we found that PSD-93 deficiency reduced infarcted volume and neurological deficits induced by transient middle cerebral artery occlusion (tMCAO) in the mice. To identify novel targets of PSD-93 related neurotoxicity, we applied isobaric tags for relative and absolute quantitative (iTRAQ) labeling and combined this labeling with on-line two-dimensional LC/MS/MS technology to elucidate the changes in protein expression in PSD-93 knockout mice following tMCAO...
March 2016: Neurotoxicology
See-Ying Tam, Jennifer N Lilla, Ching-Cheng Chen, Janet Kalesnikoff, Mindy Tsai
Nerve growth factor (NGF) binds to its cognate receptor TrkA and induces neuronal differentiation by activating distinct downstream signal transduction events. RabGEF1 (also known as Rabex-5) is a guanine nucleotide exchange factor for Rab5, which regulates early endosome fusion and vesicular trafficking in endocytic pathways. Here, we used the antisense (AS) expression approach to induce an NGF-dependent sustained knockdown of RabGEF1 protein expression in stable PC12 transfectants. We show that RabGEF1 is a negative regulator of NGF-induced neurite outgrowth and modulates other cellular and signaling processes that are activated by the interaction of NGF with TrkA receptors, such as cell cycle progression, cessation of proliferation, and activation of NGF-mediated downstream signaling responses...
2015: PloS One
Stephanie A Barnes, Lasani S Wijetunge, Adam D Jackson, Danai Katsanevaki, Emily K Osterweil, Noboru H Komiyama, Seth G N Grant, Mark F Bear, U Valentin Nägerl, Peter C Kind, David J A Wyllie
UNLABELLED: Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene...
November 11, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Sandra Giovanoli, Ulrike Weber-Stadlbauer, Manfred Schedlowski, Urs Meyer, Harald Engler
Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre- and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring...
July 2016: Brain, Behavior, and Immunity
Ayse Dosemeci, Dana Toy, Thomas S Reese, Jung-Hwa Tao-Cheng
AIDA-1 is highly enriched in postsynaptic density (PSD) fractions and is considered a major component of the PSD complex. In the present study, immunogold electron microscopy was applied to determine localization as well as the activity-induced redistribution of AIDA-1 at the PSD using two antibodies that recognize two different epitopes. In cultured rat hippocampal neurons under basal conditions, immunogold label for AIDA-1 is mostly located within the dense core of the PSD, with a median distance of ~30 nm from the postsynaptic membrane...
2015: PloS One
Juan F Codocedo, Carla Montecinos-Oliva, Nibaldo C Inestrosa
Wnt-5a is a synaptogenic factor that modulates glutamatergic synapses and generates neuroprotection against Aβ oligomers. It is known that Wnt-5a plays a key role in the adult nervous system and synaptic plasticity. Emerging evidence indicates that miRNAs are actively involved in the regulation of synaptic plasticity. Recently, we showed that Wnt-5a is able to control the expression of several miRNAs including miR-101b, which has been extensively studied in carcinogenesis. However, its role in brain is just beginning to be explored...
2015: Frontiers in Cellular Neuroscience
Michael J Parker, Alan E Fryer, Deborah J Shears, Katherine L Lachlan, Shane A McKee, Alex C Magee, Shehla Mohammed, Pradeep C Vasudevan, Soo-Mi Park, Valérie Benoit, Damien Lederer, Isabelle Maystadt, Ddd Study, David R FitzPatrick
De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase-activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi-gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss-of-function (3 nonsense; 3 frameshift; 1 whole gene deletion)...
October 2015: American Journal of Medical Genetics. Part A
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