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Restorative Effects of the TrkB agonist 7,8-Dihydroxyflavone on Neuronal Network Activity in an in vitro model of Huntington's disease

2016; Frontiers Media; Volume: 10; Linguagem: Inglês

10.3389/conf.fnins.2016.93.00082

1662-4548

Alberto Capurro, Bali�o Pablo, Baez Candise, Sano Ayaka, Luthi-Carter Ruth,

Genetic Neurodegenerative Diseases

Event Abstract Back to Event Restorative Effects of the TrkB agonist 7,8-Dihydroxyflavone on Neuronal Network Activity in an in vitro model of Huntington's disease Alberto Capurro1*, Pablo Baliño1, Candise Baez1, Ayaka Sano2 and Ruth Luthi-Carter1 1 University of Leicester, Department of Neuroscience, Psychology and Behavior, United Kingdom 2 Hokkaido University, Japan Motivation Impaired transcription and transport of brain-derived neurotrophic factor (BDNF) have been strongly implicated in the pathogenesis of HuntingtonÕs disease (HD) [1,2]. Here we assess the possibility that the TrkB agonist 7,8-Dihydroxyflavone (7,8-DHF) [3] rescues HD-related changes in neuronal activity. Methods We compared micro-electrode array (MEA) recordings of a cellular model of HD comprised of rat P0 cortical neurons transfected with lentiviral vectors encoding an 171 aa fragment of either a normal (N171-18Q, 18Q) protein or disease-causing mutant (N171-82Q, 82Q) human Huntingtin protein [2]. The spike detection and data analyses were performed with customized R and Matlab codes run using the cluster machine of Leicester University (ÒAliceÓ). Results Population spike time histograms of selected examples of MEA recordings are shown in Fig. 1. They were examined together with their corresponding raster plots. Statistical comparisons of the three groups (18Q and 82Q with N = 7 MEAs, and 82Q+7,8-DHF with N = 4 MEAs) are depicted in Fig. 2. We confirmed previous results showing that the number and size of population bursts (PBs) decreases in 82Q cells. Moreover we show that treatment with the TrkB agonist 7,8-Dihydroxyflavone (7,8-DHF) can partially rescue the abnormal electrophysiological phenotype of 82Q cells, as has been previously shown in studies with BDNF. 82Q cells showed decreased spike counts, decreased burst numbers and burst intensities (Hz x active channels) and decreased mean correlation between the channels. 7,8-DHF treatment (50 nM) restored the spike counts and burst numbers (Fig. 2). Discussion and Conclusions This study confirmed our labÕs previous data showing that the number and size of PBs decreases in 82Q cells when compared to control (18Q) cells. Treatment with 7,8-DHF can significantly rescue the abnormal electrophysiological phenotypes of 82Q cells, showing an effect size similar to BDNF. Our results highlight the utility of MEAs as an in vitro model for studying HD, and indicate that 7,8-DHF or other TrkB agonists may have potential as HD treatments that restore synaptic connectivity in abnormal neuronal circuits. To further assess the role of connection probability and synaptic weight on the bursting behavior we will perform numerical simulations of randomly connected neural networks with excitatory and inhibitory neurons including adaptation using NEST (http://www.nest-initiative.org/). Acknowledgements The authors thank Dr Sandro Perrone for useful comments regarding data analysis. Supported by European CommissionÕs Seventh Framework Program FP7-PEOPLE-2011-IAPP project number 286403 Ð NEUROACT. References [1] Canals et al. (2004) J Neurosci. 24:7727-7739. [2] Gambazzi L et al. (2010) J. Pharmacol Exp Ther 335:13-22. [3] Liu X et al. (2010) J. Med. Chem. 53:8274-8286 Figure legends Fig. 1. Spike time histograms of population activity in cases of 18Q (red), 82Q (blue) and 82Q+7,8-DHF (green). The plots show 100 s of a total recording lasting 945 s. Bin size = 50 ms with a sliding step of 1 ms. Fig. 2. Statistical comparison of 4 selected parameters derived from MEA recordings (t-test with FDR calculated over 16 original parameters). Asterisks above the 82Q (blue) bars indicate differences compared to 18Q (red), whereas asterisks above the 82Q+7,8-DHF (green) bars indicate differences compared to 82Q (blue). ** FDR p values < 0.05, * FDR p values < 0.1. N = 7 MEAs for 18Q and 82Q, and 4 MEAs for 82Q+7,8-DHF. Figure 1 Keywords: BDNF, Huntington's disease, 7, bursting, Synaptic connectivity, 8-DHF Conference: MEA Meeting 2016 | 10th International Meeting on Substrate-Integrated Electrode Arrays, Reutlingen, Germany, 28 Jun - 1 Jul, 2016. Presentation Type: oral Topic: MEA Meeting 2016 Citation: Capurro A, Baliño P, Baez C, Sano A and Luthi-Carter R (2016). Restorative Effects of the TrkB agonist 7,8-Dihydroxyflavone on Neuronal Network Activity in an in vitro model of Huntington's disease. Front. Neurosci. Conference Abstract: MEA Meeting 2016 | 10th International Meeting on Substrate-Integrated Electrode Arrays. doi: 10.3389/conf.fnins.2016.93.00082 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Jun 2016; Published Online: 24 Jun 2016. * Correspondence: Dr. Alberto Capurro, University of Leicester, Department of Neuroscience, Psychology and Behavior, Leicester, United Kingdom, ac331@le.ac.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Alberto Capurro Pablo Baliño Candise Baez Ayaka Sano Ruth Luthi-Carter Google Alberto Capurro Pablo Baliño Candise Baez Ayaka Sano Ruth Luthi-Carter Google Scholar Alberto Capurro Pablo Baliño Candise Baez Ayaka Sano Ruth Luthi-Carter PubMed Alberto Capurro Pablo Baliño Candise Baez Ayaka Sano Ruth Luthi-Carter Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.