White Rose University Consortium logo
University of Leeds logo University of Sheffield logo York University logo

GABAergic regulation of proliferation in the postnatal spinal cord

New, Lauryn Emma (2019) GABAergic regulation of proliferation in the postnatal spinal cord. PhD thesis, University of Leeds.

[img] Text
New_LE_School of Biomedical Sciences_PhD_2019.pdf - Final eThesis - complete (pdf)
Restricted until 1 August 2021.

Request a copy


Ependymal cells (ECs) of the central canal (CC) are a quiescent population of neural stem cells (NSCs) present in the intact spinal cord. Normally dormant ECs are activated by injury; exhibiting increased proliferation, migration, and differentiation. Astrocytes and oligodendrocytes also generate new progeny in the intact and injured postnatal spinal cord. Understanding how the microenvironment of the spinal cord modulates proliferation and differentiation is essential if we are to consider harnessing endogenous mechanisms such as these to aid spinal cord repair. This project aims to investigate the role that the neurotransmitter GABA may play in modulating proliferation and differentiation in the adult spinal cord. Alterations in the levels of ambient γ-aminobutyric acid (GABA) in the spinal cord in vigabatrin- treated or GAD67-GFP mice resulted in either a decrease or an increase in the number of proliferating EdU+ cells in the white matter (WM), grey matter (GM), and CC compared to control, respectively. In the postnatal spinal cord there appears to be an inverse relationship between GABAergic signalling and the number of proliferating cells. Potentiation of GABAaR by the central benzodiazepine (BZ) recognition site (CBR) ligands etifoxine and midazolam also increased the number of EdU+ cells compared to vehicle. The endogenous CBR site ligand diazepam binding inhibitor (DBI) was found to be expressed in the spinal cord, with robust expression in ECs, suggesting the presence of an intrinsic mechanism which modulates the basal inhibitory GABAergic tone to restrict proliferation. Indeed, animals with alteration in ligand binding at the CBR site as a result of either flumazenil treatment, Ro15-4513 treatment, or G2F77I mutation possessed greater numbers of EdU+ cells compared to control animals. Flumazenil treatment also increased proliferation after lysophosphatidylcholine (LPC) -induced demyelination in the dorsal column. The effect of GABAergic modulation upon differentiation was varied, and its contribution to differentiation of specific cell types in the spinal cord was unclear. This study shows that GABA both positively and negatively influences proliferation in the postnatal spinal cord and that endogenous ligands such as DBI may be instrumental in the restrictive nature of GABA. Work presented here provides a basis for further study into how modulation of GABAaR by endogenous ligands such as DBI may also influence spinal cord self-regeneration and recovery.

Item Type: Thesis (PhD)
Keywords: GABA Spinal cord Proliferation
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds)
Depositing User: Miss L E New
Date Deposited: 08 Jul 2019 12:52
Last Modified: 08 Jul 2019 12:52
URI: http://etheses.whiterose.ac.uk/id/eprint/24384

Please use the 'Request a copy' link(s) above to request this thesis. This will be sent directly to someone who may authorise access.
You can contact us about this thesis. If you need to make a general enquiry, please see the Contact us page.

Actions (repository staff only: login required)