TY - THES AU - Tóth, Estilla Zsófia TI - Different Aspects of Electrophysiological and Quantitative Electron Microscopic Investigations in the Rat and the Human Neocortex PY - 2024 DO - 10.14753/SE.2024.2926 UR - https://m2.mtmt.hu/api/publication/35057347 ID - 35057347 LA - English DB - MTMT ER - TY - JOUR AU - Horváth, Ágoston Csaba AU - Mórocz, Ákos AU - Csomai, Borbála AU - Szabó, Ágnes AU - Balogh-Lantos, Zsófia AU - Fürjes, Péter AU - Tóth, Estilla Zsófia AU - Fiáth, Richárd AU - Fekete, Zoltán TI - Silicon Optrode with a Micromirror‐Tip Providing Tunable Beam Profile During Infrared Neuromodulation of the Rat Neocortex JF - ADVANCED MATERIALS TECHNOLOGIES J2 - ADV MATER TECHNOL-US VL - 9 PY - 2024 IS - 20 PG - 13 SN - 2365-709X DO - 10.1002/admt.202400044 UR - https://m2.mtmt.hu/api/publication/35087576 ID - 35087576 AB - Infrared (IR) neuromodulation holds an increasing potential in brain research, which is fueled by novel neuroengineering approaches facilitating the exploration of the biophysical mechanism in the microscale. The group lays down the fundamentals of spatially controlled optical manipulation of inherently temperature‐sensitive neuronal populations. The concept and in vivo validation of a multifunctional, optical stimulation microdevice is presented, which expands the capabilities of conventional optrodes by coupling IR light through a monolithically integrated parabolic micromirror. Heat distribution in the irradiated volume is experimentally analyzed, and the performance of the integrated electrophysiological recording components of the device is tested in the neocortex of anesthetized rodents. Evoked single‐cell responses upon IR irradiation through the novel microtool are evaluated in multiple trials. The safe operation of the implanted device is also presented using immunohistological methods. The results confirm that shift in temperature distribution in the vicinity of the optrode tip can be controlled by the integrated photonic components, and in parallel with the optical stimulation, the device is suitable to interrogate the evoked electrophysiological activity at the single neuron level. The customizable and scalable optrode system provides a new pathway to tailor the location of the heat maximum during infrared neural stimulation. LA - English DB - MTMT ER - TY - CONF AU - Tóth, Estilla Zsófia AU - Stelcz, Rebeka AU - Bod, Réka AU - Szalai, Liza AU - Bagó, Attila György AU - Nagy, Gábor AU - Tóth, Kinga AU - Ulbert, István AU - Wittner, Lucia TI - Neuronal preservation and glial cell changes in human brain organotypic slice cultures T2 - FENS Forum 2024 PY - 2024 UR - https://m2.mtmt.hu/api/publication/35775214 ID - 35775214 LA - English DB - MTMT ER - TY - JOUR AU - Szepesi Kovács, Dénes AU - Chiovini, Balázs AU - Müller, Dalma AU - Tóth, Estilla Zsófia AU - Fülöp, Anna AU - Ábrányi-Balogh, Péter AU - Wittner, Lucia AU - Várady, György AU - Farkas, Ödön AU - Turczel, Gábor AU - Katona, Gergely AU - Győrffy, Balázs AU - Keserű, György Miklós AU - Mucsi, Zoltán AU - Rózsa J., Balázs AU - Kovács, Ervin TI - Synthesis and Application of Two-Photon Active Fluorescent Rhodol Dyes for Antibody Conjugation and In Vitro Cell Imaging JF - ACS OMEGA J2 - ACS OMEGA VL - 8 PY - 2023 IS - 25 SP - 22836 EP - 22843 PG - 8 SN - 2470-1343 DO - 10.1021/acsomega.3c01796 UR - https://m2.mtmt.hu/api/publication/34015800 ID - 34015800 N1 - Funding Agency and Grant Number: National Office of Science, Innovation and Technology (NKFIH) [2018-1.3.1-VKE-2018-00032, KFI-18-2018-00097, TKP2021-EGA-42, 2020-1.1.5-GYORSITOSAV-2021-00004, TKP2021-NVA-14]; New National Excellence Program of the Ministry for Innovation and Technology [NKFIH PD124598, BO/799/21/7]; Janos Bolyai Research Scholarship [UNKP-22-ME3] Funding text: The research was supported by the 2018-1.3.1-VKE-2018-00032, KFI-18-2018-00097, TKP2021-EGA-42, 2020-1.1.5-GYORSITOSAV-2021-00004, and TKP2021-NVA-14 grants of the National Office of Science, Innovation and Technology (NKFIH). We are grateful for the support of NKFIH PD124598 and UNKP-19-3-I-BME-408 New National Excellence Program of the Ministry for Innovation and Technology and Janos Bolyai Research Scholarship (BO/799/21/7, UNKP-22-ME3). The authors acknowledge the supportive work of Krisztina Nemeth. We are grateful for the possibility to use ELKH Cloud, which helped us achieve the results published in this paper. LA - English DB - MTMT ER - TY - JOUR AU - Bod, Réka AU - Tóth, Kinga AU - ESSAM Fawzy Ahmed Aly, Nour AU - Tóth, Estilla Zsófia AU - Erőss, Loránd AU - Entz, László AU - Bagó, Attila György AU - Fabó, Dániel AU - Ulbert, István AU - Wittner, Lucia TI - Synaptic alterations and neuronal firing in human epileptic neocortical excitatory networks JF - FRONTIERS IN SYNAPTIC NEUROSCIENCE J2 - FRONT SYNAPTIC NEURO VL - 15 PY - 2023 PG - 22 SN - 1663-3563 DO - 10.3389/fnsyn.2023.1233569 UR - https://m2.mtmt.hu/api/publication/34093583 ID - 34093583 N1 - eCollection AB - Epilepsy is a prevalent neurological condition, with underlying neuronal mechanisms involving hyperexcitability and hypersynchrony. Imbalance between excitatory and inhibitory circuits, as well as histological reorganization are relatively well-documented in animal models or even in the human hippocampus, but less is known about human neocortical epileptic activity. Our knowledge about changes in the excitatory signaling is especially scarce, compared to that about the inhibitory cell population. This study investigated the firing properties of single neurons in the human neocortex in vitro , during pharmacological blockade of glutamate receptors, and additionally evaluated anatomical changes in the excitatory circuit in tissue samples from epileptic and non-epileptic patients. Both epileptic and non-epileptic tissues exhibited spontaneous population activity (SPA), NMDA receptor antagonization reduced SPA recurrence only in epileptic tissue, whereas further blockade of AMPA/kainate receptors reversibly abolished SPA emergence regardless of epilepsy. Firing rates did not significantly change in excitatory principal cells and inhibitory interneurons during pharmacological experiments. Granular layer (L4) neurons showed an increased firing rate in epileptic compared to non-epileptic tissue. The burstiness of neurons remained unchanged, except for that of inhibitory cells in epileptic recordings, which decreased during blockade of glutamate receptors. Crosscorrelograms computed from single neuron discharge revealed both mono- and polysynaptic connections, particularly involving intrinsically bursting principal cells. Histological investigations found similar densities of SMI-32-immunopositive long-range projecting pyramidal cells in both groups, and shorter excitatory synaptic active zones with a higher proportion of perforated synapses in the epileptic group. These findings provide insights into epileptic modifications from the perspective of the excitatory system and highlight discrete alterations in firing patterns and synaptic structure. Our data suggest that NMDA-dependent glutamatergic signaling, as well as the excitatory synaptic machinery are perturbed in epilepsy, which might contribute to epileptic activity in the human neocortex. LA - English DB - MTMT ER - TY - JOUR AU - Szepesi Kovács, Dénes AU - Kontra, Bence AU - Chiovini, Balázs AU - Müller, Dalma AU - Tóth, Estilla Zsófia AU - Ábrányi-Balogh, Péter AU - Wittner, Lucia AU - Várady, György AU - Turczel, Gábor AU - Farkas, Ödön AU - Owen, Michael Christopher AU - Katona, Gergely AU - Győrffy, Balázs AU - Keserű, György Miklós AU - Mucsi, Zoltán AU - Rózsa J., Balázs AU - Kovács, Ervin TI - Effective Synthesis, Development and Application of a Highly Fluorescent Cyanine Dye for Antibody Conjugation and Microscopy Imaging JF - ORGANIC & BIOMOLECULAR CHEMISTRY J2 - ORG BIOMOL CHEM VL - 21 PY - 2023 IS - 44 SP - 8829 EP - 8836 PG - 8 SN - 1477-0520 DO - 10.1039/D3OB01471A UR - https://m2.mtmt.hu/api/publication/34205650 ID - 34205650 N1 - Funding Agency and Grant Number: National Office of Science, Innovation and Technology (NKFIH) [2018-1.3.1-VKE-2018-00032, KFI-18-2018-00097, TKP2021-EGA-42, TKP2021-NVA-15, 2020-1.1.5-GYORSITOSAV-2021-00004, 2020-2.1.1-ED-2021-00190, 2020-2.1.1-ED-2022-00208, TKP2021-NVA-14]; Janos Bolyai Research Scholarship [BO/799/21/7, UNKP-22-ME3] Funding text: This research was supported by the 2018-1.3.1-VKE-2018-00032, KFI-18-2018-00097, TKP2021-EGA-42, TKP2021-NVA-15, 2020-1.1.5-GYORSITOSAV-2021-00004, 2020-2.1.1-ED-2021-00190, 2020-2.1.1-ED-2022-00208 and TKP2021-NVA-14 grants of the National Office of Science, Innovation and Technology (NKFIH). We are grateful for the support from the Janos Bolyai Research Scholarship (BO/799/21/7, UNKP-22-ME3). The authors acknowledge the supportive work of Krisztina Nemeth. On behalf of the Development and mechanistic study of DNA dyes (PI: Dr Ervin Kovacs, ELKH Research Centre for Natural Sciences) project we are grateful for the possibility to use ELKH Cloud,53 which helped us achieve the results published in this paper. AB - An asymmetric cyanine-type fluorescent dye was designed and synthesized via a versatile, multi-step process, aiming to conjugate with an Her2+ receptor specific antibody by an azide-alkyne click reaction. The aromaticity and the excitation and relaxation energetics of the fluorophore were characterized by computational methods. The synthesized dye exhibited excellent fluorescence properties for confocal microscopy, offering efficient applicability in in vitro imaging due to its merits such as a high molar absorption coefficient (36 816 M-1 cm-1), excellent brightness, optimal wavelength (627 nm), larger Stokes shift (26 nm) and appropriate photostability compared to cyanines. The conjugated cyanine-trastuzumab was constructed via an effective, metal-free, strain-promoted azide-alkyne click reaction leading to a regulated number of dyes being conjugated. This novel cyanine-labelled antibody was successfully applied for in vitro confocal imaging and flow cytometry of Her2+ tumor cells. An azido cyanine dye was synthesized and characterized by computational and experimental techniques and applied in tumor cell imaging. LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Estilla Zsófia AU - Szabó, Felicia Gyöngyvér AU - Kandrács, Ágnes AU - Molnár, Noémi Orsolya AU - Nagy, Gábor AU - Bagó, Attila György AU - Erőss, Loránd AU - Fabó, Dániel AU - Hajnal, Boglárka Zsófia AU - Rácz, Bence AU - Wittner, Lucia AU - Ulbert, István AU - Tóth, Kinga TI - Perisomatic Inhibition and Its Relation to Epilepsy and to Synchrony Generation in the Human Neocortex JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 1 PG - 27 SN - 1661-6596 DO - 10.3390/ijms23010202 UR - https://m2.mtmt.hu/api/publication/32556740 ID - 32556740 N1 - Research Center for Natural Sciences, Institute of Cognitive Neuroscience and Psychology, Eötvös Loránd Research Network, Budapest, 1117, Hungary Semmelweis University, Szentágothai János Doctoral School, Budapest, 1026, Hungary Faculty of Information Technology and Bionics, Péter Pázmány Catholic University, Budapest, 1083, Hungary National Institute of Mental Health, Neurology and Neurosurgery, Budapest, 1145, Hungary Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, 1078, Hungary Export Date: 13 May 2022 Correspondence Address: Wittner, L.; Research Center for Natural Sciences, Hungary; email: wittner.lucia@ttk.hu Chemicals/CAS: parvalbumin, 56094-12-3, 83667-75-8; Parvalbumins; Receptors, Cannabinoid Funding details: 00002 Funding details: European Commission, EC Funding details: European Social Fund, ESF, 00008 Funding details: National Research, Development and Innovation Office, K119443, K137886, KKP126998, PD121123 Funding text 1: This research was funded by the National Research, Development, and Innovation Office, grant nos. K119443, PD121123, KKP126998 and K137886; by the Hungarian Brain Research Program, grant nos. 2017?1.2.1?NKP?2017?00002 and KTIA?NAP17?3?2017?0001; and by the EU and the European Social Fund, grant no.EFOP?3.6.2?16?2017?00008. Authors are grateful to Bal?zs Markia for providing human tissue, to Luca Barnaf?ldi for help in organizing the surgeries. AB - Inhibitory neurons innervating the perisomatic region of cortical excitatory principal cells are known to control the emergence of several physiological and pathological synchronous events, including epileptic interictal spikes. In humans, little is known about their role in synchrony generation, although their changes in epilepsy have been thoroughly investigated. This paper demonstraits how parvalbumin (PV)- and type 1 cannabinoid receptor (CB1R)-positive perisomatic interneurons innervate pyramidal cell bodies, and their role in synchronous population events spontaneously emerging in the human epileptic and non-epileptic neocortex, in vitro. Quantitative electron microscopy showed that the overall, PV+ and CB1R+ somatic inhibitory inputs remained unchanged in focal cortical epilepsy. On the contrary, the size of PV-stained synapses increased, and their number decreased in epileptic samples, in synchrony generating regions. Pharmacology demonstrated-in conjunction with the electron microscopy-that although both perisomatic cell types participate, PV+ cells have stronger influence on the generation of population activity in epileptic samples. The somatic inhibitory input of neocortical pyramidal cells remained almost intact in epilepsy, but the larger and consequently more efficient somatic synapses might account for a higher synchrony in this neuron population. This, together with epileptic hyperexcitability, might make a cortical region predisposed to generate or participate in hypersynchronous events. LA - English DB - MTMT ER - TY - JOUR AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Vagrys, Darius AU - Imre, Timea AU - Varró, Nikolett AU - Mándity, István AU - Rácz, Anita AU - Wittner, Lucia AU - Tóth, Kinga AU - Tóth, Estilla Zsófia AU - Juhász, Tünde AU - Davis, Ben AU - Keserű, György Miklós TI - A covalent strategy to target intrinsically disordered proteins: Discovery of novel tau aggregation inhibitors JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 231 PY - 2022 PG - 13 SN - 0223-5234 DO - 10.1016/j.ejmech.2022.114163 UR - https://m2.mtmt.hu/api/publication/32649994 ID - 32649994 AB - Intrinsically disordered proteins (IDPs) play important roles in disease pathologies; however, their lack of defined stable 3D structures make traditional drug design strategies typically less effective against these targets. Based on promising results of targeted covalent inhibitors (TCIs) on challenging targets, we have developed a covalent design strategy targeting IDPs. As a model system we chose tau, an endogenous IDP of the central nervous system that is associated with severe neurodegenerative diseases via its aggregation. First, we mapped the tractability of available cysteines in tau and prioritized suitable warheads. Next, we introduced the selected vinylsulfone warhead to the non-covalent scaffolds of potential tau aggregation inhibitors. The designed covalent tau binders were synthesized and tested in aggregation models, and inhibited tau aggregation effectively. Our results revealed the usefulness of the covalent design strategy against therapeutically relevant IDP targets and provided promising candidates for the treatment of tauopathies. LA - English DB - MTMT ER - TY - JOUR AU - Hofer, Katharina AU - Kandrács, Ágnes AU - Tóth, Kinga AU - Hajnal, Boglárka Zsófia AU - Bokodi, Virág AU - Tóth, Estilla Zsófia AU - Erőss, Loránd AU - Entz, László AU - Bagó, Attila György AU - Fabó, Dániel AU - Ulbert, István AU - Wittner, Lucia TI - Bursting of excitatory cells is linked to interictal epileptic discharge generation in humans. JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 12 PY - 2022 IS - 1 PG - 17 SN - 2045-2322 DO - 10.1038/s41598-022-10319-4 UR - https://m2.mtmt.hu/api/publication/32785453 ID - 32785453 N1 - Funding Agency and Grant Number: ELKH Research Centre for Natural Sciences; Postdoctoral fellowship of the Hungarian Academy of Sciences; Hungarian Brain Research Program [KTIA_13_NAP-A-IV/1-4,6, KTIA 13 NAP-A-I/1, 2017-1.2.1-NKP-2017-00002, KTIA_NAP_13-1-2013-0001, KTIA-NAP17-3-2017-0001]; Hungarian National Research Fund [OTKA K119443, K137886, PD121123] Funding text: Open access funding provided by ELKH Research Centre for Natural Sciences. This study was supported by the Postdoctoral fellowship of the Hungarian Academy of Sciences (to K. T.), by the Hungarian Brain Research Program, KTIA_13_NAP-A-IV/1-4,6, KTIA 13 NAP-A-I/1 and 2017-1.2.1-NKP-2017-00002 (to I. U.) and KTIA_NAP_13-1-2013-0001, KTIA-NAP17-3-2017-0001 (to D. F.), and by the Hungarian National Research Fund OTKA K119443 and K137886 (to L. W.) and PD121123 (to K. T.) grants. AB - Knowledge about the activity of single neurons is essential in understanding the mechanisms of synchrony generation, and particularly interesting if related to pathological conditions. The generation of interictal spikes-the hypersynchronous events between seizures-is linked to hyperexcitability and to bursting behaviour of neurons in animal models. To explore its cellular mechanisms in humans we investigated the activity of clustered single neurons in a human in vitro model generating both physiological and epileptiform synchronous events. We show that non-epileptic synchronous events resulted from the finely balanced firing of excitatory and inhibitory cells, which was shifted towards an enhanced excitability in epileptic tissue. In contrast, interictal-like spikes were characterised by an asymmetric overall neuronal discharge initiated by excitatory neurons with the presumptive leading role of bursting pyramidal cells, and possibly terminated by inhibitory interneurons. We found that the overall burstiness of human neocortical neurons is not necessarily related to epilepsy, but the bursting behaviour of excitatory cells comprising both intrinsic and synaptically driven bursting is clearly linked to the generation of epileptiform synchrony. LA - English DB - MTMT ER - TY - JOUR AU - Szepesi Kovács, Dénes AU - Hajdu, Imre AU - Mészáros, Gergely AU - Wittner, Lucia AU - Meszéna, Domokos AU - Tóth, Estilla Zsófia AU - Hegedűs, Zita AU - Randelovic, Ivan AU - Tóvári, József AU - Szabó, Tímea AU - Szilágyi, Bence AU - Milen, Mátyás AU - Keserű, György Miklós AU - Ábrányi-Balogh, Péter TI - Synthesis and characterization of new fluorescent boro-β-carboline dyes JF - RSC ADVANCES J2 - RSC ADV VL - 11 PY - 2021 IS - 21 SP - 12802 EP - 12807 PG - 6 SN - 2046-2069 DO - 10.1039/D1RA02132J UR - https://m2.mtmt.hu/api/publication/31951354 ID - 31951354 N1 - Research Centre for Natural Sciences, Medicinal Chemistry Research Group, Budapest, POB 286, Hungary Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, 1521, Hungary Research Centre for Natural Sciences, Comparative Psychophysiology Research Group, Budapest, POB 286, Hungary Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, POB 278, Hungary János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, 1085, Hungary National Institute of Oncology, Department of Experimental Pharmacology, POB 21, Budapest, 1525, Hungary Egis Pharmaceuticals Plc., Directorate of Drug Substance Development, POB 100, Budapest, 1475, Hungary Export Date: 30 August 2021 CODEN: RSCAC Correspondence Address: Keserű, G.M.; Research Centre for Natural Sciences, POB 286, Hungary; email: keseru.gyorgy@ttk.hu LA - English DB - MTMT ER -