@article{MTMT:3144889, title = {Fast 3D Imaging of Spine, Dendritic, and Neuronal Assemblies in Behaving Animals.}, url = {https://m2.mtmt.hu/api/publication/3144889}, author = {Szalay, Gergely and Judák, Linda and Katona, Gergely and Ocsai, K and Juhász, Gábor and Veress, Máté and Szadai, Zoltán and Fehér, András and Tompa, Tamás and Chiovini, Balázs and Maák, Pál and Rózsa J., Balázs}, doi = {10.1016/j.neuron.2016.10.002}, journal-iso = {NEURON}, journal = {NEURON}, volume = {92}, unique-id = {3144889}, issn = {0896-6273}, abstract = {Understanding neural computation requires methods such as 3D acousto-optical (AO) scanning that can simultaneously read out neural activity on both the somatic and dendritic scales. AO point scanning can increase measurement speed and signal- to-noise ratio (SNR) by several orders of magnitude, but high optical resolution requires long point-to-point switching time, which limits imaging capability. Here we present a novel technology, 3D DRIFT AO scanning, which can extend each scanning point to small 3D lines, surfaces, or volume elements for flexible and fast imaging of complex structures simultaneously in multiple locations. Our method was demonstrated by fast 3D recording of over 150 dendritic spines with 3D lines, over 100 somata with squares and cubes, or multiple spiny dendritic segments with surface and volume elements, including in behaving animals. Finally, a 4-fold improvement in total excitation efficiency resulted in about 500 x 500 x 650 mum scanning volume with genetically encoded calcium indicators (GECIs).}, year = {2016}, eissn = {1097-4199}, pages = {723-738}, orcid-numbers = {Katona, Gergely/0000-0002-4173-0355} } @article{MTMT:2812783, title = {Amyloid-β1-42 disrupts synaptic plasticity by altering glutamate recycling at the synapse}, url = {https://m2.mtmt.hu/api/publication/2812783}, author = {Varga, Edina and Juhász, Gábor and Bozsó, Zsolt and Penke, Botond and Fülöp, Lívia and Szegedi, Viktor}, doi = {10.3233/JAD-142367}, journal-iso = {J ALZHEIMERS DIS}, journal = {JOURNAL OF ALZHEIMER'S DISEASE}, volume = {45}, unique-id = {2812783}, issn = {1387-2877}, abstract = {Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disorders characterized by neuritic plaques containing amyloid-beta peptide (Abeta) and neurofibrillary tangles. Evidence has been reported that Abeta1-42 plays an essential pathogenic role in decreased spine density, impairment of synaptic plasticity, and neuronal loss with disruption of memory-related synapse function, all associated with AD. Experimentally, Abeta1-42 oligomers perturb hippocampal long-term potentiation (LTP), an electrophysiological correlate of learning and memory. Abeta was also reported to perturb synaptic glutamate (Glu)-recycling by inhibiting excitatory-amino-acid-transporters. Elevated level of extracellular Glu leads to activation of perisynaptic receptors, including NR2B subunit containing NMDARs. These receptors were shown to induce impaired LTP and enhanced long-term depression and proapoptotic pathways, all central features of AD. In the present study, we investigated the role of Glu-recycling on Abeta1-42-induced LTP deficit in the CA1. We found that Abeta-induced LTP damage, which was mimicked by the Glu-reuptake inhibitor TBOA, could be rescued by blocking the NR2B subunit of NMDA receptors. Furthermore, decreasing the level of extracellular Glu using a Glu scavenger also restores TBOA or Abeta induces LTP damage. Overall, these results suggest that reducing ambient Glu in the brain can be protective against Abeta-induced synaptic disruption.}, keywords = {Brain; ARTICLE; MOUSE; priority journal; controlled study; nonhuman; animal tissue; animal model; animal experiment; LONG-TERM POTENTIATION; synapse; n methyl dextro aspartic acid receptor; glutamic acid; unclassified drug; Alzheimer's disease; aspartic acid; SCAVENGER; nerve cell plasticity; amyloid beta protein[1-42]; ifenprodil; long term potentiation; pyruvate sodium; dextro levo threo beta benzyloxyaspartate; TBOA; NR2B; glutamate-reuptake; glutamate scavenger}, year = {2015}, eissn = {1875-8908}, pages = {449-456}, orcid-numbers = {Bozsó, Zsolt/0000-0002-5713-3096; Penke, Botond/0000-0003-0938-0567; Fülöp, Lívia/0000-0002-8010-0129; Szegedi, Viktor/0000-0003-4191-379X} } @article{MTMT:2755870, title = {Abeta(1-42) Enhances Neuronal Excitability in the CA1 via NR2B Subunit-Containing NMDA Receptors}, url = {https://m2.mtmt.hu/api/publication/2755870}, author = {Varga, Edina and Juhász, Gábor and Bozsó, Zsolt and Penke, Botond and Fülöp, Lívia and Szegedi, Viktor}, doi = {10.1155/2014/584314}, journal-iso = {NEURAL PLAST}, journal = {NEURAL PLASTICITY}, volume = {2014}, unique-id = {2755870}, issn = {2090-5904}, abstract = {Neuronal hyperexcitability is a phenomenon associated with early Alzheimer's disease. The underlying mechanism is considered to involve excessive activation of glutamate receptors; however, the exact molecular pathway remains to be determined. Extracellular recording from the CA1 of hippocampal slices is a long-standing standard for a range of studies both in basic research and in neuropharmacology. Evoked field potentials (fEPSPs) are regarded as the input, while spiking rate is regarded as the output of the neuronal network; however, the relationship between these two phenomena is not fully clear. We investigated the relationship between spontaneous spiking and evoked fEPSPs using mouse hippocampal slices. Blocking AMPA receptors (AMPARs) with CNQX abolished fEPSPs, but left firing rate unchanged. NMDA receptor (NMDAR) blockade with MK801 decreased neuronal spiking dose dependently without altering fEPSPs. Activating NMDARs by small concentration of NMDA induced a trend of increased firing. These results suggest that fEPSPs are mediated by synaptic activation of AMPARs, while spontaneous firing is regulated by the activation of extrasynaptic NMDARs. Synaptotoxic Abeta(1-42) increased firing activity without modifying evoked fEPSPs. This hyperexcitation was prevented by ifenprodil, an antagonist of the NR2B NMDARs. Overall, these results suggest that Abeta(1-42) induced neuronal overactivity is not dependent on AMPARs but requires NR2B.}, year = {2014}, eissn = {1687-5443}, orcid-numbers = {Bozsó, Zsolt/0000-0002-5713-3096; Penke, Botond/0000-0003-0938-0567; Fülöp, Lívia/0000-0002-8010-0129; Szegedi, Viktor/0000-0003-4191-379X} } @article{MTMT:2365063, title = {Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice}, url = {https://m2.mtmt.hu/api/publication/2365063}, author = {Tóth, Erzsébet Melinda and Szegedi, Viktor and Varga, Edina and Juhász, Gábor and Horváth, János and Borbély, Emőke and Csibrány, Balázs and Alföldi, Róbert and Lénárt, Nikolett and Penke, Botond and Sántha, Miklós}, doi = {10.1007/s12192-013-0428-9}, journal-iso = {CELL STRESS CHAPERON}, journal = {CELL STRESS & CHAPERONES}, volume = {18}, unique-id = {2365063}, issn = {1355-8145}, abstract = {Hsp27 belongs to the small heat shock protein family, which are ATP-independent chaperones. The most important function of Hsp27 is based on its ability to bind non-native proteins and inhibit the aggregation of incorrectly folded proteins maintaining them in a refolding-competent state. Additionally, it has anti-apoptotic and antioxidant activities. To study the effect of Hsp27 on memory and synaptic functions, amyloid-β (Aβ) accumulation, and neurodegeneration, we generated transgenic mice overexpressing human Hsp27 protein and crossed with APPswe/PS1dE9 mouse strain, a mouse model of Alzheimer's disease (AD). Using different behavioral tests, we found that spatial learning was impaired in AD model mice and was rescued by Hsp27 overexpression. Electrophysiological recordings have revealed that excitability of neurons was significantly increased, and long-term potentiation (LTP) was impaired in AD model mice, whereas they were normalized in Hsp27 overexpressing AD model mice. Using anti-amyloid antibody, we counted significantly less amyloid plaques in the brain of APPswe/PS1dE9/Hsp27 animals compared to AD model mice. These results suggest that overexpression of Hsp27 protein might ameliorate certain symptoms of AD. © 2013 Cell Stress Society International.}, keywords = {TRANSGENIC MICE; Alzheimer's disease; MOUSE MODEL; Heat shock proteins; Electrophysiological recordings; Real-time Q-PCR; Behavior tests; Amyloid plaques}, year = {2013}, eissn = {1466-1268}, pages = {759-771}, orcid-numbers = {Szegedi, Viktor/0000-0003-4191-379X; Lénárt, Nikolett/0000-0002-7456-949X; Penke, Botond/0000-0003-0938-0567} } @article{MTMT:2101104, title = {Increased Tau Phosphorylation and Impaired Presynaptic Function in Hypertriglyceridemic ApoB-100 Transgenic Mice}, url = {https://m2.mtmt.hu/api/publication/2101104}, author = {Lénárt, Nikolett and Szegedi, Viktor and Juhász, Gábor and Kasztner, Anikó and Horváth, János and Bereczki, Erika and Tóth, Erzsébet Melinda and Penke, Botond and Sántha, Miklós}, doi = {10.1371/journal.pone.0046007}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {7}, unique-id = {2101104}, issn = {1932-6203}, abstract = {Aims: ApoB-100 is the major protein component of cholesterol- and triglyceride-rich LDL and VLDL lipoproteins in the serum. Previously, we generated and partially described transgenic mice overexpressing the human ApoB-100 protein. Here, we further characterize this transgenic strain in order to reveal a possible link between hypeprlipidemia and neurodegeneration. Methods and Results: We analyzed the serum and cerebral lipid profiles, tau phosphorylation patterns, amyloid plaque-formation, neuronal apoptosis and synaptic plasticity of young (3 month old), adult (6 month old) and aging (10-11 month old) transgenic mice. We show that ApoB-100 transgenic animals present i) elevated serum and cerebral levels of triglycerides and ApoB-100, ii) increased cerebral tau phosphorylation at phosphosites Ser 199, Ser 199/202, Ser 396 and Ser 404. Furthermore, we demonstrate, that tau hyperphosphorylation is accompanied by impaired presynaptic function, long-term potentiation and widespread hippocampal neuronal apoptosis. Conclusions: The results presented here indicate that elevated ApoB-100 level and the consequent chronic hypertriglyceridemia may lead to impaired neuronal function and neurodegeneration, possibly via hyperphosphorylation of tau protein. On account of their specific phenotype, ApoB-100 transgenic mice may be considered a versatile model of hyperlipidemia-induced age-related neurodegeneration. © 2012 Lénárt et al.}, year = {2012}, eissn = {1932-6203}, orcid-numbers = {Lénárt, Nikolett/0000-0002-7456-949X; Szegedi, Viktor/0000-0003-4191-379X; Penke, Botond/0000-0003-0938-0567} } @article{MTMT:2034805, title = {A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic Beta-Amyloid Oligomers}, url = {https://m2.mtmt.hu/api/publication/2034805}, author = {Fülöp, Lívia and Mándity, István and Juhász, Gábor and Szegedi, Viktor and Hetényi, Anasztázia and Wéber, Edit and Bozsó, Zsolt and Simon, Dóra and Benkő, Mária and Király, Zoltán and Martinek, Tamás}, doi = {10.1371/journal.pone.0039485}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {7}, unique-id = {2034805}, issn = {1932-6203}, abstract = {Background and Aims

Unnatural self-organizing biomimetic polymers (foldamers) emerged as promising materials for biomolecule recognition and inhibition. Our goal was to construct multivalent foldamer-dendrimer conjugates which wrap the synaptotoxic β-amyloid (Aβ) oligomers with high affinity through their helical foldamer tentacles. Oligomeric Aβ species play pivotal role in Alzheimer's disease, therefore recognition and direct inhibition of this undruggable target is a great current challenge.

Methods and Results

Short helical β-peptide foldamers with designed secondary structures and side chain chemistry patterns were applied as potential recognition segments and their binding to the target was tested with NMR methods (saturation transfer difference and transferred-nuclear Overhauser effect). Helices exhibiting binding in the µM region were coupled to a tetravalent G0-PAMAM dendrimer. In vitro biophysical (isothermal titration calorimetry, dynamic light scattering, transmission electron microscopy and size-exclusion chromatography) and biochemical tests (ELISA and dot blot) indicated the tight binding between the foldamer conjugates and the Aβ oligomers. Moreover, a selective low nM interaction with the low molecular weight fraction of the Aβ oligomers was found. Ex vivo electrophysiological experiments revealed that the new material rescues the long-term potentiation from the toxic Aβ oligomers in mouse hippocampal slices at submicromolar concentration.

Conclusions

The combination of the foldamer methodology, the fragment-based approach and the multivalent design offers a pathway to unnatural protein mimetics that are capable of specific molecular recognition, and has already resulted in an inhibitor for an extremely difficult target.

}, keywords = {Neurotoxicity; hippocampus; ARTICLE; MOUSE; controlled study; nonhuman; animal tissue; Protein Binding; in vitro study; POLYMER; unclassified drug; binding affinity; chemical structure; Biophysics; BIOCHEMISTRY; ex vivo study; Oligomer; Nuclear magnetic resonance spectroscopy; protein interaction; amyloid beta protein; chemical binding; long term potentiation; dendrimer; foldamer}, year = {2012}, eissn = {1932-6203}, orcid-numbers = {Fülöp, Lívia/0000-0002-8010-0129; Mándity, István/0000-0003-2865-6143; Szegedi, Viktor/0000-0003-4191-379X; Hetényi, Anasztázia/0000-0001-8080-6992; Wéber, Edit/0000-0002-5904-0619; Bozsó, Zsolt/0000-0002-5713-3096; Martinek, Tamás/0000-0003-3168-8066} } @article{MTMT:1848719, title = {GluA1 phosphorylation alters evoked firing pattern in vivo}, url = {https://m2.mtmt.hu/api/publication/1848719}, author = {Barkóczi, Balázs Zoltán and Juhász, Gábor and Averkin, Róbert and Voros, Imre and Vertes, Petra and Penke, Botond and Szegedi, Viktor}, doi = {10.1155/2012/286215}, journal-iso = {NEURAL PLAST}, journal = {NEURAL PLASTICITY}, volume = {2012}, unique-id = {1848719}, issn = {2090-5904}, year = {2012}, eissn = {1687-5443}, orcid-numbers = {Barkóczi, Balázs Zoltán/0000-0003-1760-2035; Penke, Botond/0000-0003-0938-0567; Szegedi, Viktor/0000-0003-4191-379X} } @article{MTMT:1842703, title = {Tianeptine potentiates AMPA receptors by activating CaMKII and PKA via the p38, p42/44 MAPK and JNK pathways}, url = {https://m2.mtmt.hu/api/publication/1842703}, author = {Szegedi, Viktor and Juhász, Gábor and Zhang, XQ and Barkóczi, Balázs Zoltán and Qi, HS and Madeira, A and Kapus, G and Svenningsson, P and Spedding, M and Penke, Botond}, doi = {10.1016/j.neuint.2011.10.008}, journal-iso = {NEUROCHEM INT}, journal = {NEUROCHEMISTRY INTERNATIONAL}, volume = {59}, unique-id = {1842703}, issn = {0197-0186}, abstract = {Impairments of cellular plasticity appear to underlie the pathophysiology of major depression. Recently, elevated levels of phosphorylated AMPA receptor were implicated in the antidepressant effect of various drugs. Here, we investigated the effects of an antidepressant, Tianeptine, on synaptic function and GluA1 phosphorylation using murine hippocampal slices and in vivo single-unit recordings. Tianeptine, but not imipramine, increased AMPA receptor-mediated neuronal responses both in vitro and in vivo, in a stauro-sporine-sensitive manner. Paired-pulse ratio was unaltered by Tianeptine, suggesting a postsynaptic site of action. Tianeptine, 10 mu M, enhanced the GluA1-dependent initial phase of LIP, whereas 100 mu M impaired the latter phases, indicating a critical role of GluA1 subunit phosphorylation in the excitation. Tianeptine rapidly increased the phosphorylation level of Ser(831)-GluA1 and Ser(845)-GluA1. Using H-89 and KN-93, we show that the activation of both PKA and CaMKII is critical in the effect of Tianeptine on AMPA responses. Moreover, the phosphorylation states of Ser(217/221)-MEK and Thr(183)/Tyr(185)-p42MAPK were increased by Tianeptine and specific kinase blockers of the MAPK pathways (PD 98095, SB 203580 and SP600125) prevented the effects of Tianeptine. Overall these data suggest that Tianeptine potentiates several signaling cascades associated with synaptic plasticity and provide further evidence that a major mechanism of action for Tianeptine is to act as an enhancer of glutamate neurotransmission via AMPA receptors. (C) 2011 Elsevier B.V. All rights reserved.}, keywords = {FRONTAL-CORTEX; PHOSPHORYLATION; IN-VITRO; STRESS; DEPRESSION; GLUTAMATE RECEPTORS; SYNAPTIC PLASTICITY; LONG-TERM POTENTIATION; NMDA; RAT HIPPOCAMPUS; SIGNALING PATHWAY; Antidepressant; KINASE CASCADE; ANTIDEPRESSANT DRUG; DRUG DISCOVERY}, year = {2011}, eissn = {1872-9754}, pages = {1109-1122}, orcid-numbers = {Szegedi, Viktor/0000-0003-4191-379X; Barkóczi, Balázs Zoltán/0000-0003-1760-2035; Penke, Botond/0000-0003-0938-0567} } @article{MTMT:1627330, title = {Functional changes in transcriptomes of the prefrontal cortex and hippocampus in a mouse model of anxiety}, url = {https://m2.mtmt.hu/api/publication/1627330}, author = {Virók, Dezső and Kis, Z and Szegedi, Viktor and Juhász, Gábor and Zvara, Ágnes and Muller, G and Lévay, György István and Hársing, László Gábor and Rajkó, Róbert and Penke, Botond and Janka, Zoltán and Janáky, Tamás and Puskás, László}, doi = {10.1016/S1734-1140(11)70501-1}, journal-iso = {PHARMACOL REP}, journal = {PHARMACOLOGICAL REPORTS}, volume = {63}, unique-id = {1627330}, issn = {1734-1140}, keywords = {Animals; Male; MICE; NEUROPEPTIDE; prefrontal cortex; hippocampus; ARTICLE; MOUSE; Pathogenesis; Cell Differentiation; Up-Regulation; cross breeding; Genetic Predisposition to Disease; gene mutation; controlled study; nonhuman; animal tissue; animal model; animal experiment; Mice, Inbred Strains; synaptic transmission; Behavior, Animal; animal behavior; Gene Expression; Gene Expression Profiling; Disease Models, Animal; Down-Regulation; ion transport; Drug targeting; MOUSE MODEL; anxiety; disease activity; genetic predisposition; gene identification; upregulation; microarray; anxiety disorder; functional morphology; down regulation; gene function; potassium ion; glia cell; nervous system development; intracellular signaling; peptidergic nervous system; Wnt protein}, year = {2011}, eissn = {2299-5684}, pages = {348-361}, orcid-numbers = {Szegedi, Viktor/0000-0003-4191-379X; Hársing, László Gábor/0000-0003-1670-8591; Rajkó, Róbert/0000-0002-6234-658X; Penke, Botond/0000-0003-0938-0567; Janáky, Tamás/0000-0002-6466-8283} } @{MTMT:1878910, title = {ICV injected Aβ-peptide induces dysfunctions in hippocampus and in spatial memory: model for Alzheimer's disease}, url = {https://m2.mtmt.hu/api/publication/1878910}, author = {Kasza, Ágnes and Szegedi, Viktor and Juhász, Gábor and Frank, Zsuzsanna and Penke, Zsuzsa and Penke, Botond}, booktitle = {The 5th Central European Conference "Chemistry towards Biology"}, unique-id = {1878910}, year = {2010}, pages = {98}, orcid-numbers = {Szegedi, Viktor/0000-0003-4191-379X; Penke, Botond/0000-0003-0938-0567} }