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Understanding how voltage- and ligand-gated ion channels influence the behaviour of cells of the oligodendrocyte lineage

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Ricci, RP ORCID: 0000-0001-8722-8021 2021 , 'Understanding how voltage- and ligand-gated ion channels influence the behaviour of cells of the oligodendrocyte lineage', PhD thesis, University of Tasmania.

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Abstract

Throughout life, oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into new myelinating oligodendrocytes. As OPCs express ionotropic glutamate receptors and voltage-gated channels, they are able to detect and respond to neuronal activity. In this context, N-Methyl-D-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor bind glutamate and alters the behaviour of cells of the oligodendrocyte lineage, however, the requirement of kainate receptors and voltage-gated calcium channels (VGCC) remains unclear. In Chapter 1 of this thesis, I review the regulatory the role of ion channels and ionotropic receptors in oligodendrogenesis. In Chapter 2, I characterise the expression of VGCCs by adult OPCs and demonstrate their capacity to influence adult OPC survival. In Chapter 3, I explore the importance of kainate receptor for OPC generation and myelination and examine their role within the central nervous system (CNS). In Chapter 4, I outline my research findings and describe how this research has informed my research goals and understanding of the relationship between neuronal activity and myelination.
Research findings:
In Chapter 2, I conditionally deleted Cacna1c, a gene encoding the VGCC CaV1.2, from OPCs in the adult mouse brain. Tamoxifen was delivered to P60 Cacna1c\(^{fl/fl}\) (control) and Pdgfrα-CreER :: Cacna1c\(^{fl/fl}\) (CaV1.2-deleted) mice and whole cell patch clamp recordings revealed that CaV1.2 deletion reduced L-type voltage-gated calcium entry into adult OPCs by ~60%. The conditional deletion of CaV1.2 from adult OPCs significantly increased their proliferation but did not affect the number of new oligodendrocytes produced or influence the length or number of internodes they elaborated. Unexpectedly, CaV1.2 deletion resulted in the dramatic loss of OPCs from the corpus callosum, such that 7 days after tamoxifen administration CaV1.2-deleted mice had an OPC density ~42% that of control mice. However, OPC density recovered within 2 weeks of CaV1.2 deletion, as the lost OPCs were replaced by surviving CaV1.2-deleted OPCs. As OPC density was not affected in the motor cortex or spinal cord, I have concluded that calcium entry through CaV1.2 is a critical survival signal for a subpopulation of callosal OPCs, but not for all OPCs, in the mature CNS.
In Chapter 3, I show that Grik4 mRNA is highly expressed by cells throughout the adult mouse brain, and the loss of this gene (Grik4 knockout mice; Grik4 \(^{-/-}\)) reduces anxiety- and depressive-like behaviour and progressively impair motor function. Such phenotypes can be produced by demyelination, however, OPC and oligodendrocyte numbers are normal in Grik4 -/- mice. While myelination is also normal in Grik4\(^{-/-}\) mice, and callosal compound action potentials (CAP) travel at normal velocity, their amplitude is reduced. However, subtle axonal abnormalities were detected and layer 5 pyramidal neurons in the primary motor cortex received significantly fewer synaptic inputs. Therefore, Gluk4-containing kainate receptors are critical for motor circuit maintenance and consequently motor function in adult mice.

Item Type: Thesis - PhD
Authors/Creators:Ricci, RP
Keywords: Neuroscience, Glial Biology, voltage-gated calcium channel, kainate receptors, ion channels, neural circuits, OPCs, oligodendrocytes
DOI / ID Number: 10.25959/100.00045489
Copyright Information:

Copyright 2021 the author.

Additional Information:

Chapter 2 appears to be the equivalent of a post-print version of an article published as: Pitman, K. A., Ricci, R., Gasperini, R., Beasley, S., Pavez, M., Charlesworth, J., Foa, L., Young, K. M., 2020. The voltage-gated calcium channel CaV1.2 promotes adult oligodendrocyte progenitor cell survival in the mouse corpus callosum but not motor cortex, Glia, 68(2), 376– 392. © 2019 the authors. Glia published by Wiley Periodicals, Inc. This is an open access article published under a Creative Commons (Attribution 4.0 International (CC BY 4.0) license, (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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