Publications by authors named "Theofilos Papadopoulos"

39 Publications

The α3 subunit of GABA receptors promotes formation of inhibitory synapses in the absence of collybistin.

J Biol Chem 2021 Apr 23:100709. Epub 2021 Apr 23.

Universitätsmedizin Göttingen, Department of Molecular Biology, Humboldtallee 23, 37075 Göttingen, Germany. Electronic address:

Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects - or synaptopathies - are at the basis of many neurological and psychiatric disorders. Collybistin (CB), a brain-specific guanine nucleotide exchange factor (GEF), is essential for the formation of γ-aminobutyric acidergic (GABAergic) postsynapses in defined regions of the mammalian forebrain, including the hippocampus and the basolateral amygdala. This process depends on a direct interaction of CB with the scaffolding protein gephyrin, which leads to the redistribution of gephyrin into submembranous clusters at nascent inhibitory synapses. Strikingly, synaptic clustering of gephyrin and GABA receptors (GABARs) in several brain regions, including the cerebral cortex and certain thalamic areas, is unperturbed in CB-deficient mice, indicating that the formation of a substantial subset of inhibitory postsynapses must be controlled by gephyrin-interacting proteins other than CB. Previous studies indicated that the α3 subunit of GABARs (GABAR-α3) binds directly and with high affinity to gephyrin. Here, we provide evidence (i) that a homooligomeric GABAR-α3 mutant induces the formation of submembranous gephyrin clusters independently of CB in COS-7 cells, (ii) that gephyrin clustering is unaltered in the neuronal subpopulations endogenously expressing the GABAR-α3 in CB-deficient brains, and (iii) that exogenous expression of GABAR-α3 partially rescues impaired gephyrin clustering in CB-deficient hippocampal neurons. Our results identify an important role of GABAR-α3 in promoting gephyrin-mediated and CB-independent formation of inhibitory postsynapses.
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http://dx.doi.org/10.1016/j.jbc.2021.100709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141935PMC
April 2021

The Rising Burden of Salmonellosis Caused by Monophasic Typhimurium (1,4,[5],12:i:-) in Greece and New Food Vehicles.

Antibiotics (Basel) 2021 Feb 13;10(2). Epub 2021 Feb 13.

Department of Foodborne and Waterborne Diseases, National Public Health Organization, 15123 Athens, Greece.

Monophasic is of increasing importance worldwide. Here we present the available data regarding monophasic from 2007 to 2019 in Greece, in order to assess its public health impact. Surveillance data, data on antimicrobial resistance, molecular typing by pulsed-field gel electrophoresis (PFGE), and results of the investigation of monophasic . outbreaks were analyzed. Overall, 403 cases were identified; 329 (81.6%) sporadic and 74 (18.4%) related to two community outbreaks in 2017. A total of 305 isolates from sporadic cases tested for antimicrobial resistance revealed resistance to ampicillin, streptomycin, sulphamethoxazole, and tetracycline (41.3%). Some 23.3% were further resistant to trimethoprim and 5.2% were also resistant to chloramphenicol. Outbreak 1 in 2017 with 37 identified cases was attributed to the consumption of raw milk from a vending machine and isolates were resistant to ampicillin, streptomycin, sulphamethoxazole, tetracycline, and trimethoprim. Outbreak 2 also with 37 cases was attributed to the consumption of pork and isolates were resistant to the five above mentioned antibiotics plus chloramphenicol. The number of human monophasic . isolates is low; however, since 2009, it has been among the five most frequently identified serotypes in Greece. Investigation of the outbreaks revealed that other vehicles apart from pork may be implicated in the occurrence of outbreaks.
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http://dx.doi.org/10.3390/antibiotics10020185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917691PMC
February 2021

Collybistin SH3-protein isoforms are expressed in the rat brain promoting gephyrin and GABA-A receptor clustering at GABAergic synapses.

J Neurochem 2021 05 5;157(4):1032-1051. Epub 2021 Jan 5.

Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, USA.

Collybistin (CB) is a guanine nucleotide exchange factor (GEF) selectively localized at GABAergic and glycinergic postsynapses. Analysis of mRNA shows that several isoforms of collybistin are expressed in the brain. Some of the isoforms have a SH3 domain (CBSH3+) and some have no SH3 domain (CBSH3-). The CBSH3+ mRNAs are predominantly expressed over CBSH3-. However, in an immunoblot study of mouse brain homogenates, only CBSH3+ protein isoforms were detected, proposing that CBSH3- protein might not be expressed in the brain. The expression or lack of expression of CBSH3- protein is an important issue because CBSH3- has a strong effect in promoting the postsynaptic clustering of gephyrin and GABA-A receptors (GABA Rs). Moreover CBSH3- is constitutively active; therefore lower expression of CBSH3- protein might play a relatively stronger functional role than the more abundant but self-inhibited CBSH3+ isoforms, which need to be activated. We are now showing that: (a) CBSH3- protein is expressed in the brain; (b) parvalbumin positive (PV+) interneurons show higher expression of CBSH3- protein than other neurons; (c) CBSH3- is associated with GABAergic synapses in various regions of the brain and (d) knocking down CBSH3- in hippocampal neurons decreases the synaptic clustering of gephyrin and GABA Rs. The results show that CBSH3- protein is expressed in the brain and that it plays a significant role in the size regulation of the GABAergic postsynapse.
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http://dx.doi.org/10.1111/jnc.15270DOI Listing
May 2021

Neuroligin-2 dependent conformational activation of collybistin reconstituted in supported hybrid membranes.

J Biol Chem 2020 12 30;295(52):18604-18613. Epub 2020 Oct 30.

Institute for Organic and Biomolecular Chemistry, Georg August University, Göttingen, Germany; Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany. Electronic address:

The assembly of the postsynaptic transmitter sensing machinery at inhibitory nerve cell synapses requires the intimate interplay between cell adhesion proteins, scaffold and adaptor proteins, and γ-aminobutyric acid (GABA) or glycine receptors. We developed an membrane system to reconstitute this process, to identify the essential protein components, and to define their mechanism of action, with a specific focus on the mechanism by which the cytosolic of the synaptic cell adhesion protein Neuroligin-2 alters the conformation of the adaptor protein Collybistin-2 and thereby controls Collybistin-2-interactions with phosphoinositides (PtdInsPs) in the plasma membrane. Supported hybrid membranes doped with different PtdInsPs and 1,2-dioleoyl--glycero-3-{[-(5-amino-1-carboxypentyl)iminodiacetic acid]succinyl} nickel salt (DGS-NTA(Ni)) to allow for the specific adsorption of the His-tagged intracellular domain of Neuroligin-2 (His-NL2) were prepared on hydrophobically functionalized silicon dioxide substrates via vesicle spreading. Two different collybistin variants, the WT protein (CB2) and a mutant that adopts an intrinsically 'open' and activated conformation (CB2), were bound to supported membranes in the absence or presence of His-NL2. The corresponding binding data, obtained by reflectometric interference spectroscopy, show that the interaction of the of Neuroligin-2 with Collybistin-2 induces a conformational change in Collybistin-2 that promotes its interaction with distinct membrane PtdInsPs.
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http://dx.doi.org/10.1074/jbc.RA120.015347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939476PMC
December 2020

A GTPase-induced switch in phospholipid affinity of collybistin contributes to synaptic gephyrin clustering.

J Cell Sci 2020 01 23;133(2). Epub 2020 Jan 23.

Department of Molecular Biology, Universitätsmedizin Göttingen, Humboldtallee 23, Göttingen 37073, Germany

Synaptic transmission between neurons relies on the exact spatial organization of postsynaptic transmitter receptors, which are recruited and positioned by dedicated scaffolding and regulatory proteins. At GABAergic synapses, the regulatory protein collybistin (Cb, also known as ARHGEF9) interacts with small GTPases, cell adhesion proteins and phosphoinositides to recruit the scaffolding protein gephyrin and GABA receptors to nascent synapses. We dissected the interaction of Cb with the small Rho-like GTPase TC10 (also known as RhoQ) and phospholipids. Our data define a protein-lipid interaction network that controls the clustering of gephyrin at synapses. Within this network, TC10 and monophosphorylated phosphoinositides, particulary phosphatidylinositol 3-phosphate (PI3P), provide a coincidence detection platform that allows the accumulation and activation of Cb in endomembranes. Upon activation, TC10 induces a phospholipid affinity switch in Cb, which allows Cb to specifically interact with phosphoinositide species present at the plasma membrane. We propose that this GTPase-based regulatory switch mechanism represents an important step in the process of tethering of Cb-dependent scaffolds and receptors at nascent postsynapses.
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http://dx.doi.org/10.1242/jcs.232835DOI Listing
January 2020

Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) in bulk tank milk, livestock and dairy-farm personnel in north-central and north-eastern Greece: Prevalence, characterization and genetic relatedness.

Food Microbiol 2019 Dec 22;84:103249. Epub 2019 Jun 22.

Laboratory of Hygiene of Foods of Animal Origin-Veterinary Public Health, School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.

Recently, there has been an increased tendency towards raw-milk consumption, which may pose a consumer risk, due to the possible presence of human pathogenic microorganisms, such as Staphylococcus aureus and even methicillin-resistant S. aureus (MRSA). The prevalence of S. aureus and methicillin-resistant S. aureus (MRSA) was investigated in 40 dairy (cattle, sheep and goat) farms in northern Greece. S. aureus and MRSA were detected in 47.8% and 4.1% of the 387 samples (raw milk, farmers and animal samples) tested, respectively. Most (81.3%) of the MRSA isolates harbored the mecA gene, whereas the mecC or Panton-Valentine Leucocidin (PVL) genes were not detected. Seven spa types were identified, with t127 being the most prevalent. Spa type t034 (CC398) was isolated for the first time from livestock in Greece. Staphylococcal enterotoxin genes were detected in 93.8% of the MRSA isolates. The MRSA isolates were genetically diverse and were all capable of biofilm production. Our results confirm the lurking threat of MRSA in raw milk and dairy farms and suggest the need for surveillance programs starting at the farm level.
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http://dx.doi.org/10.1016/j.fm.2019.103249DOI Listing
December 2019

The health and economic impact of acute gastroenteritis in Belgium, 2010-2014.

Epidemiol Infect 2019 01;147:e146

Department of Epidemiology and Public Health,Sciensano,Brussels,Belgium.

Acute gastroenteritis (AGE) remains a common condition in both low- and high-income countries. In Belgium, however, there is currently a lack of information on the societal health and economic impact of AGE. We conducted a retrospective study using mortality and cause-of-death data, hospital data, primary care data, health interview survey data and other published data. We estimated the burden of illness during a 5-year period (2010-2014) in Belgium in terms of deaths, patients admitted to hospitals, patients consulting their general practitioner (GP) and cases occurring in the community. We further quantified the health impact in terms of disability-adjusted life years (DALYs) and the economic impact in terms of cost-of-illness estimates. We estimated 343 deaths, 27 707 hospitalised patients, 464 222 GP consultations and 10 058 741 episodes occurring in the community (0.91 cases/person) on average per year. AGE was associated with 11 855 DALYs per year (107 DALY per 100 000 persons). The economic burden was estimated to represent direct costs of €112 million, indirect costs of €927 million (90% of the total costs) and an average total cost of €103 per case and €94 per person. AGE results in a substantial health and economic impact in Belgium, justifying continued mitigation efforts.
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http://dx.doi.org/10.1017/S095026881900044XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518509PMC
January 2019

Prevalence, antimicrobial susceptibility and characterization of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus isolated from dairy industries in north-central and north-eastern Greece.

Int J Food Microbiol 2019 Feb 9;291:35-41. Epub 2018 Nov 9.

Laboratory of Hygiene of Foods of Animal Origin-Veterinary Public Health, School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.

Staphylococcus aureus is an important cause of food intoxication, whereas methicillin-resistant S. aureus (MRSA) constitutes a serious public-health concern due to its ability to colonize and infect humans and animals. S. aureus and MRSA have often been isolated from milk and dairy products. The objectives of this study were to estimate the prevalence and the antimicrobial resistance of S. aureus and MRSA in four Greek dairy industries, to identify virulence factors of MRSA isolates and to describe their genetic diversity, in order to identify possible epidemiological links and evaluate the risk of MRSA dissemination to the community. S. aureus was isolated from 67 out of 305 (22.0%) dairy industry samples (bulk-tank milk, dairy products, employee nasal swabs and equipment/surface swabs). Almost all (99%) of the 227 corresponding S. aureus isolates (approximately 4 isolates per positive sample) were resistant to at least one antimicrobial and 22% were multi-drug resistant (MDR). MRSA were isolated from 11 different samples (3.6%) originating from three of the dairy plants. All MRSA isolates were capable of forming biofilms, while staphylococcal enterotoxin (SE) genes were detected in 91% of the MRSA isolates, with sec being the most frequent. All of the MRSA isolates harbored the mecA gene but the mecC and Pandon-Valentine leucocidin (PVL) genes were not detected. Pulse-Field Gel Electrophoresis (PFGE) analysis showed genetic diversity among the MRSA isolates and indicated clonal circulation in one of the dairy plants. Seven spa types were identified among the MRSA isolates with the most prevalent (t065) isolated only in one dairy plant. Certain spa types (t065, t337 and t3536) were isolated for the first time in Greece. The presence of MDR, biofilm-forming and enterotoxigenic MRSA strains in dairy plant facilities may lead to their dissemination to the community, but also to staphylococcal food poisoning, when conditions are favorable. The study's findings highlight the need for continuous monitoring of the dairy production chain, the need for re-evaluating the implemented cleaning and sanitizing processes and the adoption of preventive strategies in order to minimize public-health risks.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2018.11.007DOI Listing
February 2019

A computational approach for the estimation of heart failure patients status using saliva biomarkers.

Annu Int Conf IEEE Eng Med Biol Soc 2017 Jul;2017:3648-3651

The aim of this work is to present a computational approach for the estimation of the severity of heart failure (HF) in terms of New York Heart Association (NYHA) class and the characterization of the status of the HF patients, during hospitalization, as acute, progressive or stable. The proposed method employs feature selection and classification techniques. However, it is differentiated from the methods reported in the literature since it exploits information that biomarkers fetch. The method is evaluated on a dataset of 29 patients, through a 10-fold-cross-validation approach. The accuracy is 94 and 77% for the estimation of HF severity and the status of HF patients during hospitalization, respectively.
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http://dx.doi.org/10.1109/EMBC.2017.8037648DOI Listing
July 2017

Prevalence of Staphylococcus aureus and of methicillin-resistant S. aureus (MRSA) along the production chain of dairy products in north-western Greece.

Food Microbiol 2018 Feb 28;69:43-50. Epub 2017 Jul 28.

Laboratory of Hygiene of Foods of Animal Origin, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.

The objective of this study was to estimate the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the production chain of dairy products. Of 367 tested samples (36 bulk tank milk (BTM), 19 dairy products, 72 human, 185 animal, 55 equipment), 212 (57.8%) were found positive for S. aureus. Almost all isolates (99.6%) were resistant to at least one antimicrobial and 13.3% were multi-drug resistant (MDR), exhibiting resistance to three or more antibiotic classes. Eleven samples (3%) were found contaminated by MRSA carrying the mecA gene. None of the MRSA isolates carried the mecC or the Pandon-Valentine leucocidin (PVL) genes. Four spa types were identified among the MRSA isolates: t127, t3586, t1773, t4038, with t127 being the most prevalent (7 out of 11). Two of them, t3586 and t1773, were isolated for the first time in Greece. Furthermore, Pulse-Field Gel Electrophoresis (PFGE) analysis indicated clonal circulation through the dairy production chain. The presence of MDR S. aureus, and especially MRSA, in animals and dairy products represents a potential threat for the spread of this pathogen in the community. The results indicated that human, animal and environmental sources could be involved in the contamination of dairy products along their production chain and therefore further investigation of contamination sources is needed to control the dispersion of MRSA in the community.
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http://dx.doi.org/10.1016/j.fm.2017.07.016DOI Listing
February 2018

Multiple clones and low antimicrobial resistance rates for Salmonella enterica serovar Infantis populations in Greece.

Comp Immunol Microbiol Infect Dis 2017 Apr 31;51:54-58. Epub 2017 Mar 31.

National Reference Centre for Salmonella, National School of Public Health & Central Public Health Laboratory, Hellenic Centre of Disease Control and Prevention, 16672, Vari, Greece.

All the Salmonella enterica ser. Infantis strains isolated under official control programs in Greece during a four year period were studied, 23 of human origin, 16 from food animals and one from food. Molecular analyses (PFGE) in combination with antimicrobial susceptibility testing were used to study whether the occurrence S. Infantis in Greece resulted from different biotypes or a successful spread of one clone. Low rates of antimicrobial resistance were observed, except for streptomycin among human isolates (48%), indicating that selective pressure due to consumption of antimicrobials has not resulted the spread of dominant clones. Pulsed Field Gel Electrophoresis revealed 31 XbaI distinct pulsotypes among the 40 strains with 60% overall similarity reflecting diversity. Four main clusters were constructed, using an 85% cut off value, clusters A, B, C and D consisting of 14, 6, 8 and 8 isolates respectively. Point source of transmission was not hypothesized as multiple reservoirs of the serovar seem to be present in Greece during the study period.
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http://dx.doi.org/10.1016/j.cimid.2017.02.002DOI Listing
April 2017

Organizers of inhibitory synapses come of age.

Curr Opin Neurobiol 2017 08 28;45:66-77. Epub 2017 Apr 28.

Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein-Straße 3, 37075 Göttingen, Germany.

While the postsynaptic density of excitatory synapses is known to encompass a highly complex molecular machinery, the equivalent organizational structure of inhibitory synapses has long remained largely undefined. In recent years, however, substantial progress has been made towards identifying the full complement of organizational proteins present at inhibitory synapses, including submembranous scaffolds, intracellular signaling proteins, transsynaptic adhesion proteins, and secreted factors. Here, we summarize these findings and discuss future challenges in assigning synapse-specific functions to the newly discovered catalog of proteins, an endeavor that will depend heavily on newly developed technologies such as proximity biotinylation. Further advances are made all the more essential by growing evidence that links inhibitory synapses to psychiatric and neurological disorders.
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http://dx.doi.org/10.1016/j.conb.2017.04.003DOI Listing
August 2017

Anti-microbial coating innovations to prevent infectious diseases (AMiCI): Cost action ca15114.

Bioengineered 2017 Nov 19;8(6):679-685. Epub 2017 May 19.

n Zuyd University of Applied Sciences , Heerlen , The Netherlands.

Worldwide, millions of patients are affected annually by healthcare-associated infection (HCAI), impacting up to 80,000 patients in European Hospitals on any given day. This represents not only public health risk, but also an economic burden. Complementing routine hand hygiene practices, cleaning and disinfection, antimicrobial coatings hold promise based, in essence, on the application of materials and chemicals with persistent bactericidal or -static properties onto surfaces or in textiles used in healthcare environments. The focus of considerable commercial investment and academic research energies, such antimicrobial coating-based approaches are widely believed to have potential in reduction of microbial numbers on surfaces in clinical settings. This belief exists despite definitive evidence as to their efficacy and is based somewhat on positive studies involving, for example, copper, silver or gold ions, titanium or organosilane, albeit under laboratory conditions. The literature describes successful delay and/or prevention of recontamination following conventional cleaning and disinfection by problematic microbes such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE), among others. However, there is a scarcity of studies assessing antimicrobial surfaces other than copper in the clinical environment, and a complete lack of published data regarding the successful implementation of these materials on clinically significant outcomes (including HCAI). Through its Cooperation in Science and Technology program (COST), the European Commission has funded a 4-year initiative to establish a network of stakeholders involved in development, regulation and use of novel anti-microbial coatings for prevention of HCAI. The network (AMiCI) comprises participants of more than 60 universities, research institutes and companies across 29 European countries and, to-date, represents the most comprehensive consortium targeting use of these emergent technologies in healthcare settings. More specifically, the network will prioritise coordinated research on the effects (both positive and negative) of antimicrobial coatings in healthcare sectors; know-how regarding availability and mechanisms of action of (nano)-coatings; possible adverse effects of such materials (e.g., potential emergence of microbial resistance or emission of toxic agents into the environment); standardised performance assessments for antimicrobial coatings; identification and dissemination of best practices by hospitals, other clinical facilities, regulators and manufacturers.
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http://dx.doi.org/10.1080/21655979.2017.1323593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736330PMC
November 2017

Differences in sheep and goats milk microbiological profile between conventional and organic farming systems in Greece.

J Dairy Res 2017 May 15;84(2):206-213. Epub 2017 Mar 15.

Laboratory of Hygiene and Epidemiology,Faculty of Medicine,University of Thessaly,Greece.

The aim of this study was to examine differences in the microbiological profile and antimicrobial resistance of bacteria isolated from milk from organic and conventional sheep and goat farms. Twenty-five organic and 25 conventional sheep and goat farms in the region of Thessaly, Greece participated in this study. A standardised detailed questionnaire was used to describe farming practices. A total of 50 samples were collected and analysed for total viable count (TVC), total coliform count (TCC) and somatic cell count (SCC), while Staphylococcus aureus and Escherichia coli were isolated using standard methods. Isolates were identified at species level by Api-test and Matrix-Assisted Laser Desorption/Ionisation-Time of Flight Mass Spectrometry (MALDI-TOF MS). Susceptibility to a panel of 20 for E. coli and 16 for S. aureus antimicrobials was determined by the agar dilution method. Pulsed Field Gel Electrophoresis (PFGE) was performed for S. aureus and E. coli isolates to determine predominant clones. Lower counts of TVC, TCC and SCC were identified in milk from the organic farms, possibly due to differences in the hygienic farming practices found on those farms. API-tests and MALDI-TOF MS showed no significant differences in the S. aureus and E. coli isolates. Overall, antimicrobial resistance rates were low, while a statistically higher percentage was estimated among strains originating from conventional farms in comparison with organic farms, possibly due to the restriction of antibiotic use in organic farming. PFGE revealed diversity among S. aureus and E. coli populations in both organic and conventional farms indicating circulation of 2-3 main clones changing slightly during their evolution. Consequently, there is evidence that milk from the organic farms presents a better microbiological profile when compared with milk from conventional farms.
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http://dx.doi.org/10.1017/S0022029917000103DOI Listing
May 2017

Cervical Cancer Cell Line Secretome Highlights the Roles of Transforming Growth Factor-Beta-Induced Protein ig-h3, Peroxiredoxin-2, and NRF2 on Cervical Carcinogenesis.

Biomed Res Int 2017 2;2017:4180703. Epub 2017 Feb 2.

First Department of Obstetrics and Gynecology, University of Athens School of Medicine, Alexandra Hospital, Athens, Greece; Laboratory of Cell and Gene Therapy, Biomedical Research Foundation, Academy of Athens, Athens, Greece.

Cancer cells acquire unique secretome compositions that contribute to tumor development and metastasis. The aim of our study was to elucidate the biological processes involved in cervical cancer, by performing a proteomic analysis of the secretome from the following informative cervical cell lines: SiHa (HPV16+), HeLa (HPV18+), C33A (HPV-), and HCK1T (normal). Proteins were analyzed by 2D gel electrophoresis coupled to MALDI-TOF-MS. Enrichment of secreted proteins with characteristic profiles for each cell line was followed by the identification of differentially expressed proteins. Particularly, transforming growth factor-beta-induced protein ig-h3 (Beta ig-h3) and peroxiredoxin-2 (PRDX2) overexpression in the secretome of cancer cell lines was detected and confirmed by Western blot. Bioinformatics analysis identified the transcription factor NRF2 as a regulator of differentially expressed proteins in the cervical cancer secretome. NRF2 levels were measured by both Western blot and Multiple Reaction Monitoring (MRM) in the total cell extract of the four cell lines. NRF2 was upregulated in SiHa and C33A compared to HCK1T. In conclusion, the secreted proteins identified in cervical cancer cell lines indicate that aberrant NRF2-mediated oxidative stress response (OSR) is a prominent feature of cervical carcinogenesis.
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http://dx.doi.org/10.1155/2017/4180703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316418PMC
April 2017

Systems biology combining human- and animal-data miRNA and mRNA data identifies new targets in ureteropelvic junction obstruction.

BMC Syst Biol 2017 03 1;11(1):31. Epub 2017 Mar 1.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Metabolic and Cardiovascular Diseases-I2MC, 1 avenue Jean Poulhès, B.P. 84225, 31432, Toulouse Cedex 4, France.

Background: Although renal fibrosis and inflammation have shown to be involved in the pathophysiology of obstructive nephropathies, molecular mechanisms underlying evolution of these processes remain undetermined. In an attempt towards improved understanding of obstructive nephropathy and improved translatability of the results to clinical practice we have developed a systems biology approach combining omics data of both human and mouse obstructive nephropathy.

Results: We have studied in parallel the urinary miRNome of infants with ureteropelvic junction obstruction and the kidney tissue miRNome and transcriptome of the corresponding neonatal partial unilateral ureteral obstruction (UUO) mouse model. Several hundreds of miRNAs and mRNAs displayed changed abundance during disease. Combination of miRNAs in both species and associated mRNAs let to the prioritization of five miRNAs and 35 mRNAs associated to disease. In vitro and in vivo validation identified consistent dysregulation of let-7a-5p and miR-29-3p and new potential targets, E3 ubiquitin-protein ligase (DTX4) and neuron navigator 1 (NAV1), potentially involved in fibrotic processes, in obstructive nephropathy in both human and mice that would not be identified otherwise.

Conclusions: Our study is the first to correlate a mouse model of neonatal partial UUO with human UPJ obstruction in a comprehensive systems biology analysis. Our data revealed let-7a and miR-29b as molecules potentially involved in the development of fibrosis in UPJ obstruction via the control of DTX4 in both man and mice that would not be identified otherwise.
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http://dx.doi.org/10.1186/s12918-017-0411-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333413PMC
March 2017

Heart Failure: Diagnosis, Severity Estimation and Prediction of Adverse Events Through Machine Learning Techniques.

Comput Struct Biotechnol J 2017 17;15:26-47. Epub 2016 Nov 17.

Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, FORTH, GR 45110 Ioannina, Greece; Unit of Medical Technology and Intelligent Information Systems, University of Ioannina, GR 45110 Ioannina, Greece.

Heart failure is a serious condition with high prevalence (about 2% in the adult population in developed countries, and more than 8% in patients older than 75 years). About 3-5% of hospital admissions are linked with heart failure incidents. Heart failure is the first cause of admission by healthcare professionals in their clinical practice. The costs are very high, reaching up to 2% of the total health costs in the developed countries. Building an effective disease management strategy requires analysis of large amount of data, early detection of the disease, assessment of the severity and early prediction of adverse events. This will inhibit the progression of the disease, will improve the quality of life of the patients and will reduce the associated medical costs. Toward this direction machine learning techniques have been employed. The aim of this paper is to present the state-of-the-art of the machine learning methodologies applied for the assessment of heart failure. More specifically, models predicting the presence, estimating the subtype, assessing the severity of heart failure and predicting the presence of adverse events, such as destabilizations, re-hospitalizations, and mortality are presented. According to the authors' knowledge, it is the first time that such a comprehensive review, focusing on all aspects of the management of heart failure, is presented.
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http://dx.doi.org/10.1016/j.csbj.2016.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133661PMC
November 2016

Endosomal Phosphatidylinositol 3-Phosphate Promotes Gephyrin Clustering and GABAergic Neurotransmission at Inhibitory Postsynapses.

J Biol Chem 2017 01 9;292(4):1160-1177. Epub 2016 Dec 9.

the Department of Neurochemistry, Max Planck Institute for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt am Main, Germany, and.

The formation of neuronal synapses and the dynamic regulation of their efficacy depend on the proper assembly of the postsynaptic neurotransmitter receptor apparatus. Receptor recruitment to inhibitory GABAergic postsynapses requires the scaffold protein gephyrin and the guanine nucleotide exchange factor collybistin (Cb). In vitro, the pleckstrin homology domain of Cb binds phosphoinositides, specifically phosphatidylinositol 3-phosphate (PI3P). However, whether PI3P is required for inhibitory postsynapse formation is currently unknown. Here, we investigated the role of PI3P at developing GABAergic postsynapses by using a membrane-permeant PI3P derivative, time-lapse confocal imaging, electrophysiology, as well as knockdown and overexpression of PI3P-metabolizing enzymes. Our results provide the first in cellula evidence that PI3P located at early/sorting endosomes regulates the postsynaptic clustering of gephyrin and GABA receptors and the strength of inhibitory, but not excitatory, postsynapses in cultured hippocampal neurons. In human embryonic kidney 293 cells, stimulation of gephyrin cluster formation by PI3P depends on Cb. We therefore conclude that the endosomal pool of PI3P, generated by the class III phosphatidylinositol 3-kinase, is important for the Cb-mediated recruitment of gephyrin and GABA receptors to developing inhibitory postsynapses and thus the formation of postsynaptic membrane specializations.
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http://dx.doi.org/10.1074/jbc.M116.771592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270463PMC
January 2017

Predicting adherence of patients with HF through machine learning techniques.

Healthc Technol Lett 2016 Sep 27;3(3):165-170. Epub 2016 Sep 27.

Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, FORTH, GR 45110 Ioannina, Greece; Unit of Medical Technology and Intelligent Information Systems, University of Ioannina, GR 45110 Ioannina, Greece.

Heart failure (HF) is a chronic disease characterised by poor quality of life, recurrent hospitalisation and high mortality. Adherence of patient to treatment suggested by the experts has been proven a significant deterrent of the above-mentioned serious consequences. However, the non-adherence rates are significantly high; a fact that highlights the importance of predicting the adherence of the patient and enabling experts to adjust accordingly patient monitoring and management. The aim of this work is to predict the adherence of patients with HF, through the application of machine learning techniques. Specifically, it aims to classify a patient not only as medication adherent or not, but also as adherent or not in terms of medication, nutrition and physical activity (global adherent). Two classification problems are addressed: (i) if the patient is global adherent or not and (ii) if the patient is medication adherent or not. About 11 classification algorithms are employed and combined with feature selection and resampling techniques. The classifiers are evaluated on a dataset of 90 patients. The patients are characterised as medication and global adherent, based on clinician estimation. The highest detection accuracy is 82 and 91% for the first and the second classification problem, respectively.
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http://dx.doi.org/10.1049/htl.2016.0041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048333PMC
September 2016

Omics databases on kidney disease: where they can be found and how to benefit from them.

Clin Kidney J 2016 Jun 21;9(3):343-52. Epub 2016 Mar 21.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.

In the recent decades, the evolution of omics technologies has led to advances in all biological fields, creating a demand for effective storage, management and exchange of rapidly generated data and research discoveries. To address this need, the development of databases of experimental outputs has become a common part of scientific practice in order to serve as knowledge sources and data-sharing platforms, providing information about genes, transcripts, proteins or metabolites. In this review, we present omics databases available currently, with a special focus on their application in kidney research and possibly in clinical practice. Databases are divided into two categories: general databases with a broad information scope and kidney-specific databases distinctively concentrated on kidney pathologies. In research, databases can be used as a rich source of information about pathophysiological mechanisms and molecular targets. In the future, databases will support clinicians with their decisions, providing better and faster diagnoses and setting the direction towards more preventive, personalized medicine. We also provide a test case demonstrating the potential of biological databases in comparing multi-omics datasets and generating new hypotheses to answer a critical and common diagnostic problem in nephrology practice. In the future, employment of databases combined with data integration and data mining should provide powerful insights into unlocking the mysteries of kidney disease, leading to a potential impact on pharmacological intervention and therapeutic disease management.
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http://dx.doi.org/10.1093/ckj/sfv155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886900PMC
June 2016

IQ Motif and SEC7 Domain-containing Protein 3 (IQSEC3) Interacts with Gephyrin to Promote Inhibitory Synapse Formation.

J Biol Chem 2016 May 21;291(19):10119-30. Epub 2016 Mar 21.

From the Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea,

Gephyrin is a central scaffold protein that mediates development, function, and plasticity of mammalian inhibitory synapses by interacting with various inhibitory synaptic proteins. Here, we show that IQSEC3, a guanine nucleotide exchange factor for ARF6, directly interacts with gephyrin, an interaction that is critical for the inhibitory synapse localization of IQSEC3. Overexpression of IQSEC3 increases inhibitory, but not excitatory, synapse density in a guanine nucleotide exchange factor activity-dependent manner. Conversely, knockdown of IQSEC3 decreases size of gephyrin cluster without altering gephyrin puncta density. Collectively, these data reveal that IQSEC3 acts together with gephyrin to regulate inhibitory synapse development.
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http://dx.doi.org/10.1074/jbc.M115.712893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858964PMC
May 2016

Specificity of Collybistin-Phosphoinositide Interactions: IMPACT OF THE INDIVIDUAL PROTEIN DOMAINS.

J Biol Chem 2016 Jan 6;291(1):244-54. Epub 2015 Nov 6.

From the Institute of Organic and Biomolecular Chemistry, University of Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany,

The regulatory protein collybistin (CB) recruits the receptor-scaffolding protein gephyrin to mammalian inhibitory glycinergic and GABAergic postsynaptic membranes in nerve cells. CB is tethered to the membrane via phosphoinositides. We developed an in vitro assay based on solid-supported 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine membranes doped with different phosphoinositides on silicon/silicon dioxide substrates to quantify the binding of various CB2 constructs using reflectometric interference spectroscopy. Based on adsorption isotherms, we obtained dissociation constants and binding capacities of the membranes. Our results show that full-length CB2 harboring the N-terminal Src homology 3 (SH3) domain (CB2SH3+) adopts a closed and autoinhibited conformation that largely prevents membrane binding. This autoinhibition is relieved upon introduction of the W24A/E262A mutation, which conformationally "opens" CB2SH3+ and allows the pleckstrin homology domain to properly bind lipids depending on the phosphoinositide species with a preference for phosphatidylinositol 3-monophosphate and phosphatidylinositol 4-monophosphate. This type of membrane tethering under the control of the release of the SH3 domain of CB is essential for regulating gephyrin clustering.
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http://dx.doi.org/10.1074/jbc.M115.673400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697159PMC
January 2016

Lipid binding defects and perturbed synaptogenic activity of a Collybistin R290H mutant that causes epilepsy and intellectual disability.

J Biol Chem 2015 Mar 12;290(13):8256-70. Epub 2015 Feb 12.

From the Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany, and

Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects--or synaptopathies--are at the basis of many neurological and psychiatric disorders. In key areas of the mammalian brain, such as the hippocampus or the basolateral amygdala, the clustering of the scaffolding protein Gephyrin and of γ-aminobutyric acid type A receptors at inhibitory neuronal synapses is critically dependent upon the brain-specific guanine nucleotide exchange factor Collybistin (Cb). Accordingly, it was discovered recently that an R290H missense mutation in the diffuse B-cell lymphoma homology domain of Cb, which carries the guanine nucleotide exchange factor activity, leads to epilepsy and intellectual disability in human patients. In the present study, we determined the mechanism by which the Cb(R290H) mutation perturbs inhibitory synapse formation and causes brain dysfunction. Based on a combination of biochemical, cell biological, and molecular dynamics simulation approaches, we demonstrate that the R290H mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of Cb. This defect reduces the phosphatidylinositol 3-phosphate binding affinity of Cb, which limits its normal synaptogenic activity. Our data indicate that impairment of the membrane lipid binding activity of Cb and a consequent defect in inhibitory synapse maturation represent a likely molecular pathomechanism of epilepsy and mental retardation in humans.
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http://dx.doi.org/10.1074/jbc.M114.633024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375481PMC
March 2015

miRNAs in urine: a mirror image of kidney disease?

Expert Rev Mol Diagn 2015 Mar 8;15(3):361-74. Epub 2015 Feb 8.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, 1 avenue Jean Poulhès, B.P. 84225, 31432 Toulouse Cedex 4, France.

miRNAs are short non-coding RNAs that control post-transcriptional regulation of gene expression. They are found ubiquitously in tissue and body fluids and participate in the pathogenesis of many diseases. Due to these characteristics and their stability, miRNAs could serve as biomarkers of different pathologies of the kidney. Urine is a non-invasive reservoir of molecules, especially indicative of the urinary system. In this review, we focus on urinary miRNAs and their potential to serve as biomarkers in kidney disease. Past studies show that urinary miRNAs correlate with renal dysfunctions and with processes involved in the pathophysiology. However, these studies also stress the need for future research focusing on large-scale studies to confirm the usability of urinary miRNAs as diagnostic and/or prognostic markers of different kidney diseases in clinical practice.
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http://dx.doi.org/10.1586/14737159.2015.1009449DOI Listing
March 2015

A conformational switch in collybistin determines the differentiation of inhibitory postsynapses.

EMBO J 2014 Sep 30;33(18):2113-33. Epub 2014 Jul 30.

Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany

The formation of neuronal synapses and the dynamic regulation of their efficacy depend on the assembly of the postsynaptic neurotransmitter receptor apparatus. Receptor recruitment to inhibitory GABAergic and glycinergic synapses is controlled by the scaffold protein gephyrin and the adaptor protein collybistin. We derived new insights into the structure of collybistin and used these to design biochemical, cell biological, and genetic analyses of collybistin function. Our data define a collybistin-based protein interaction network that controls the gephyrin content of inhibitory postsynapses. Within this network, collybistin can adopt open/active and closed/inactive conformations to act as a switchable adaptor that links gephyrin to plasma membrane phosphoinositides. This function of collybistin is regulated by binding of the adhesion protein neuroligin-2, which stabilizes the open/active conformation of collybistin at the postsynaptic plasma membrane by competing with an intramolecular interaction in collybistin that favors the closed/inactive conformation. By linking trans-synaptic neuroligin-dependent adhesion and phosphoinositide signaling with gephyrin recruitment, the collybistin-based regulatory switch mechanism represents an integrating regulatory node in the formation and function of inhibitory postsynapses.
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http://dx.doi.org/10.15252/embj.201488143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195776PMC
September 2014

Collybistin activation by GTP-TC10 enhances postsynaptic gephyrin clustering and hippocampal GABAergic neurotransmission.

Proc Natl Acad Sci U S A 2013 Dec 2;110(51):20795-800. Epub 2013 Dec 2.

Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.

In many brain regions, gephyrin and GABAA receptor clustering at developing inhibitory synapses depends on the guanine nucleotide exchange factor collybistin (Cb). The vast majority of Cb splice variants contain an autoinhibitory src homology 3 domain, and several synaptic proteins are known to bind to this SH3 domain and to thereby activate gephyrin clustering. However, many functional GABAergic synapses form independently of the known Cb-activating proteins, indicating that additional Cb activators must exist. Here we show that the small Rho-like GTPase TC10 stimulates Cb-dependent gephyrin clustering by binding in its active, GTP-bound state to the pleckstrin homology domain of Cb. Overexpression of a constitutively active TC10 variant in neurons causes an increase in the density of synaptic gephyrin clusters and mean miniature inhibitory postsynaptic current amplitudes, whereas a dominant negative TC10 variant has opposite effects. The enhancement of Cb-induced gephyrin clustering by GTP-TC10 does not depend on the guanine nucleotide exchange activity of Cb but involves an interaction that resembles reported interactions of other small GTPases with their effectors. Our data indicate that GTP-TC10 activates the major src homology 3 domain-containing Cb variants by relieving autoinhibition and thus define an alternative GTPase-driven signaling pathway in the genesis of inhibitory synapses.
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http://dx.doi.org/10.1073/pnas.1309078110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870750PMC
December 2013

Comparison of CE-MS/MS and LC-MS/MS sequencing demonstrates significant complementarity in natural peptide identification in human urine.

Electrophoresis 2014 Apr 20;35(7):1060-4. Epub 2013 Nov 20.

Mosaiques Diagnostics, Hannover, Germany.

Clinical proteomics has led to the identification of biomarkers specifically associated with a clinical condition that can serve for diagnostic or prognostic purposes. Learning more about the origin of these protein fragments would lead to a better insight in the pathology, and this requires improved identification of the peptide sequences. The aim of this study is to assess the complementarity of LC-MS/MS and CE-MS/MS as techniques in peptide sequence identification of the urinary low-molecular weight proteome. A male standard human urine sample was analyzed using LC- and CE-MS/MS (n = 10 per technique), identifying 905 unique peptide sequences with high confidence, 50% of those were identified only with LC, 20% only with CE and 30% with both techniques. Higher LC coverage might be due in part to the higher amount of sample that can be loaded onto an LC column. Peptides uniquely identified in CE are generally small and highly charged, likely unable to bind to the LC column In conclusion, we showed that LC-MS/MS and CE-MS/MS are highly complementary in identifying peptide sequences. The combination of both technologies results in significantly increased sequence coverage.
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http://dx.doi.org/10.1002/elps.201300327DOI Listing
April 2014

IMAC fractionation in combination with LC-MS reveals H2B and NIF-1 peptides as potential bladder cancer biomarkers.

J Proteome Res 2013 Sep 21;12(9):3969-79. Epub 2013 Aug 21.

Biomedical Research Foundation Academy of Athens, Athens, Greece.

Improvement in bladder cancer (BC) management requires more effective diagnosis and prognosis of disease recurrence and progression. Urinary biomarkers attract special interest because of the noninvasive means of urine collection. Proteomic analysis of urine entails the adoption of a fractionation methodology to reduce sample complexity. In this study, we applied immobilized metal affinity chromatography in combination with high-resolution LC-MS/MS for the discovery of native urinary peptides potentially associated with BC aggressiveness. This approach was employed toward urine samples from patients with invasive BC, noninvasive BC, and benign urogenital diseases. A total of 1845 peptides were identified, corresponding to a total of 638 precursor proteins. Specific enrichment for proteins involved in nucleosome assembly and for zinc-finger transcription factors was observed. The differential expression of two candidate biomarkers, histone H2B and NIF-1 (zinc finger 335) in BC, was verified in independent sets of urine samples by ELISA and by immunohistochemical analysis of BC tissue. The results collectively support changes in the expression of both of these proteins with tumor progression, suggesting their potential role as markers for discriminating BC stages. In addition, the data indicate a possible involvement of NIF-1 in BC progression, likely as a suppressor and through interactions with Sox9 and HoxA1.
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http://dx.doi.org/10.1021/pr400255hDOI Listing
September 2013

Homeostatic regulation of gephyrin scaffolds and synaptic strength at mature hippocampal GABAergic postsynapses.

Cereb Cortex 2013 Nov 23;23(11):2700-11. Epub 2012 Aug 23.

Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University, 60590 Frankfurt am Main, Germany and.

Gephyrin is a scaffolding protein important for the postsynaptic clustering of inhibitory neurotransmitter receptors. Here, we investigated the properties of gephyrin scaffolds at γ-aminobutyric acid- (GABA-)ergic synapses in organotypic entorhino-hippocampal cultures prepared from a transgenic mouse line, which expresses green fluorescent protein-tagged gephyrin under the control of the Thy1.2 promoter. Fluorescence recovery after photobleaching revealed a developmental stabilization of postsynaptic gephyrin clusters concomitant with an increase in cluster size and synaptic strength between 1 and 4 weeks in vitro. Prolonged treatment of the slice cultures with diazepam or a GABAA receptor antagonist disclosed a homeostatic regulation of both inhibitory synaptic strength and gephyrin cluster size and stability in 4-weeks-old cultures, whereas at 1 week in vitro, the same drug treatments modulated GABAergic postsynapse and gephyrin cluster properties following a Hebbian mode of synaptic plasticity. Our data are consistent with a model in which the postnatal maturation of the hippocampal network endows CA1 pyramidal neurons with the ability to homeostatically adjust the strength of their inhibitory postsynapses to afferent GABAergic drive by regulating gephyrin scaffold properties.
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http://dx.doi.org/10.1093/cercor/bhs260DOI Listing
November 2013

The role of neurexins and neuroligins in the formation, maturation, and function of vertebrate synapses.

Curr Opin Neurobiol 2012 Jun 15;22(3):412-22. Epub 2012 Mar 15.

Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein-Straße 3, 37075 Göttingen, Germany.

Neurexins (NXs) and neuroligins (NLs) are transsynaptically interacting cell adhesion proteins that play a key role in the formation, maturation, activity-dependent validation, and maintenance of synapses. As complex alternative splicing processes in nerve cells generate a large number of NX and NLs variants, it has been proposed that a combinatorial interaction code generated by these variants may determine synapse identity and network connectivity during brain development. The functional importance of NXs and NLs is exemplified by the fact that mutations in NX and NL genes are associated with several neuropsychiatric disorders, most notably with autism. Accordingly, major research efforts have focused on the molecular mechanisms by which NXs and NLs operate at synapses. In this review, we summarize recent progress in this field and discuss emerging topics, such as the role of alternative interaction partners of NXs and NLs in synapse formation and function, and their relevance for synaptic plasticity in the mature brain. The novel findings highlight the fundamental importance of NX-NL interactions in a wide range of synaptic functions.
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http://dx.doi.org/10.1016/j.conb.2012.02.012DOI Listing
June 2012