Advanced search
1 file | 7.71 MB Add to list

Dysregulation of microtubule stability impairs morphofunctional connectivity in primary neuronal networks

Author
Organization
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.
Keywords
microtubule, primary hippocampal neuron, neuronal network, synapse, P301L, Tau aggregation, high-content microscopy, live cell imaging, TAU TRANSGENIC MICE, ALZHEIMERS-DISEASE, FRONTOTEMPORAL DEMENTIAS, COGNITIVE DEFICITS, BINDING PROPERTIES, DENDRITIC SPINES, BETA-STRUCTURE, EPOTHILONE D, MOUSE MODEL, PROTEIN

Downloads

  • 2017 Verstraelen Front Cell Neurosci.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 7.71 MB

Citation

Please use this url to cite or link to this publication:

MLA
Verstraelen, Peter et al. “Dysregulation of Microtubule Stability Impairs Morphofunctional Connectivity in Primary Neuronal Networks.” FRONTIERS IN CELLULAR NEUROSCIENCE 11 (2017): n. pag. Print.
APA
Verstraelen, P., Detrez, J. R., Verschuuren, M., Kuijlaars, J., Nuydens, R., Timmermans, J.-P., & De Vos, W. (2017). Dysregulation of microtubule stability impairs morphofunctional connectivity in primary neuronal networks. FRONTIERS IN CELLULAR NEUROSCIENCE, 11.
Chicago author-date
Verstraelen, Peter, Jan R Detrez, Marlies Verschuuren, Jacobine Kuijlaars, Rony Nuydens, Jean-Pierre Timmermans, and Winnok De Vos. 2017. “Dysregulation of Microtubule Stability Impairs Morphofunctional Connectivity in Primary Neuronal Networks.” Frontiers in Cellular Neuroscience 11.
Chicago author-date (all authors)
Verstraelen, Peter, Jan R Detrez, Marlies Verschuuren, Jacobine Kuijlaars, Rony Nuydens, Jean-Pierre Timmermans, and Winnok De Vos. 2017. “Dysregulation of Microtubule Stability Impairs Morphofunctional Connectivity in Primary Neuronal Networks.” Frontiers in Cellular Neuroscience 11.
Vancouver
1.
Verstraelen P, Detrez JR, Verschuuren M, Kuijlaars J, Nuydens R, Timmermans J-P, et al. Dysregulation of microtubule stability impairs morphofunctional connectivity in primary neuronal networks. FRONTIERS IN CELLULAR NEUROSCIENCE. 2017;11.
IEEE
[1]
P. Verstraelen et al., “Dysregulation of microtubule stability impairs morphofunctional connectivity in primary neuronal networks,” FRONTIERS IN CELLULAR NEUROSCIENCE, vol. 11, 2017.
@article{8525128,
  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.},
  articleno    = {173},
  author       = {Verstraelen, Peter and Detrez, Jan R and Verschuuren, Marlies and Kuijlaars, Jacobine and Nuydens, Rony and Timmermans, Jean-Pierre and De Vos, Winnok},
  issn         = {1662-5102},
  journal      = {FRONTIERS IN CELLULAR NEUROSCIENCE},
  keywords     = {microtubule,primary hippocampal neuron,neuronal network,synapse,P301L,Tau aggregation,high-content microscopy,live cell imaging,TAU TRANSGENIC MICE,ALZHEIMERS-DISEASE,FRONTOTEMPORAL DEMENTIAS,COGNITIVE DEFICITS,BINDING PROPERTIES,DENDRITIC SPINES,BETA-STRUCTURE,EPOTHILONE D,MOUSE MODEL,PROTEIN},
  language     = {eng},
  pages        = {16},
  title        = {Dysregulation of microtubule stability impairs morphofunctional connectivity in primary neuronal networks},
  url          = {http://dx.doi.org/10.3389/fncel.2017.00173},
  volume       = {11},
  year         = {2017},
}

Altmetric
View in Altmetric
Web of Science
Times cited: