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Title: | Dysregulation of Microtubule Stability Impairs Morphofunctional Connectivity in Primary Neuronal Networks | Authors: | Verstraelen, Peter Detrez, Jan R. Verschuuren, Marlies KUIJLAARS, Jacobine Nuydens, Rony Timmermans, Jean-Pierre De Vos, Winnok H. |
Issue Date: | 2017 | Source: | FRONTIERS IN CELLULAR NEUROSCIENCE, 11 (Art N° 173) | Abstract: | Functionally related neurons assemble into connected networks that process and transmit electrochemical information. To do this in a coordinated manner, the number and strength of synaptic connections is tightly regulated. Synapse function relies on the microtubule (MT) cytoskeleton, the dynamics of which are in turn controlled by a plethora of MT-associated proteins, including the MT-stabilizing protein Tau. Although mutations in the Tau-encodingMAPT gene underlie a set of neurodegenerative disorders, termed tauopathies, the exact contribution of MT dynamics and the perturbation thereof to neuronal network connectivity has not yet been scrutinized. Therefore, we investigated the impact of targeted perturbations of MT stability on morphological (e.g., neurite- and synapse density) and functional (e.g., synchronous calcium bursting) correlates of connectivity in networks of primary hippocampal neurons. We found that treatment with MT-stabilizing or -destabilizing compounds impaired morphofunctional connectivity in a reversible manner. We also discovered that overexpression of MAPT induced significant connectivity defects, which were accompanied by alterations in MT dynamics and increased resistance to pharmacological MT depolymerization. Overexpression of a MAPT variant harboring the P301L point mutation in the MT-binding domain did far less, directly linking neuronal connectivity with Tau's MT binding affinity. Our results show that MT stability is a vulnerable node in tauopathies and that its precise pharmacological tuning may positively affect neuronal network connectivity. However, a critical balance in MT turnover causes it to be a difficult therapeutic target with a narrow operating window. | Notes: | De Vos, WH (reprint author), Univ Antwerp, Lab Cell Biol & Histol, Dept Vet Sci, Antwerp, Belgium, winnok.devos@uantwerpen.be | Keywords: | microtubule; primary hippocampal neuron; neuronal network; synapse; P301L; Tau aggregation; high-content microscopy; live cell imaging | Document URI: | http://hdl.handle.net/1942/26259 | e-ISSN: | 1662-5102 | DOI: | 10.3389/fncel.2017.00173 | ISI #: | 000427684700001 | Rights: | Copyright © 2017 Verstraelen, Detrez, Verschuuren, Kuijlaars, Nuydens, Timmermans and De Vos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2019 |
Appears in Collections: | Research publications |
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verstraelen 1.pdf | Published version | 7.24 MB | Adobe PDF | View/Open |
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