GABAergic regulation of cell proliferation within the adult mouse spinal cord. (1st February 2023)

• Record Type: Journal Article
• Authors: New, Lauryn E.; Yanagawa, Yuchio; McConkey, Glenn A.; Deuchars, Jim; Deuchars, Susan A.
• Is Part Of: Neuropharmacology. Volume 223(2023)
• Publication Date: 2023-02-01
• Subjects: γ-aminobutyric acid -- Diazepam binding inhibitor -- Cell proliferation -- Ethynyl-2′-deoxyuridine -- Ependymal -- Spinal cord -- Neural stem cell -- Oligodendrocyte -- Astrocyte -- Differentiation; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.109326
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Manipulation of neural stem cell proliferation and differentiation in the postnatal CNS is receiving significant attention due to therapeutic potential. In the spinal cord, such manipulations may promote repair in conditions such as multiple sclerosis or spinal cord injury, but may also limit excessive cell proliferation contributing to tumours such as ependymomas. We show that when ambient γ-aminobutyric acid (GABA) is increased in vigabatrin-treated or decreased by GAD67 allele haplodeficiency in glutamic acid decarboxylase67-green fluorescent protein (GAD67-GFP) mice of either sex, the numbers of proliferating cells respectively decreased or increased. Thus, intrinsic spinal cord GABA levels are correlated with the extent of cell proliferation, providing important evidence for manipulating these levels. Diazepam binding inhibitor, an endogenous protein that interacts with GABA receptors and its breakdown product, octadecaneuropeptide, which preferentially activates central benzodiazepine (CBR) sites, were highly expressed in spinal cord, especially in ependymal cells surrounding the central canal. Furthermore, animals with reduced CBR activation via treatment with flumazenil or Ro15-4513, or with a G2F77I mutation in the CBR binding site had greater numbers of Ethynyl-2′-deoxyuridine positive cells compared to control, which maintained their stem cell status since the proportion of newly proliferated cells becoming oligodendrocytes or astrocytes was significantly lower. Altering endogenous GABA levels or modulating GABAergic signalling through specific sites on GABA receptors therefore influences NSC proliferation in the adult spinal cord. These findings provide a basis for further study into how GABAergic signalling could be manipulated to enable spinal cord self-regeneration and recovery or limit pathological proliferative activity. Graphical abstract: Image 1 Highlights: The spinal central canal (CC) is surrounded by a heterogeneous population of cells. Ependymal cells around the CC can proliferate and some exhibit neural stem cell potential. This region has high levels of the endogenous protein Diazepam Binding Inhibitor (DBI). GABAergic manipulation via DBI in vivo modulates cell proliferation and differentiation. This provides accessible ways of controlling proliferation in this stem cell niche.