GABAergic regulation of cell proliferation within the adult mouse spinal cord

New, Lauryn E; Yanagawa, Yuchio; McConkey, Glenn A.; Deuchars, Jim; Deuchars, Susan A.

doi:10.1016/j.neuropharm.2022.109326

Cited by 3 publications

(3 citation statements)

References 72 publications

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“…The implication of radial glia-like PDYN + cells in this process may explain why ependymal proliferation is triggered most prominently when the injury occurs close to the midline, rather than laterally or by a general crush (4, 39). The neurotransmitter GABA has been shown to elicit GABA A receptor-mediated electrical responses in ependymal cells (40) and restrict their proliferation (8), thus representing a likely suppressive signal released by GABAergic CSF-cNs. Interestingly, CSF-cNs express functional GABA A receptors themselves (11) and hence they may possess a feedback mechanism for autoregulating GABA release.…”

Section: Discussionmentioning

confidence: 99%

“…What action does κ signaling exert in the ependymal region? As noted above, ependymal proliferation can be inhibited by GABA (8). CSF-cNs are well poised to be the cellular origin of this GABA-mediated regulatory mechanism because they are GABAergic (20,37,38) and reside near ependymal cells.…”

Section: Tonic Activation Of Csf-cns By κ Opioids Suppresses Ependyma...mentioning

confidence: 94%

“…Following spinal cord injury, these ependymal cells divide and differentiate into astrocytes, thereby contributing to scar formation that limits secondary damage (3)(4)(5)(6)(7). Currently, it remains unknown how ependymal cell proliferation is regulated endogenously under healthy or pathological conditions, although the inhibitory neurotransmitter GABA has been suggested to be an instructive signal (8).…”

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confidence: 99%

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Endogenous Opioid Signaling Regulates Proliferation of Spinal Cord Ependymal Cells

Yue,

Touhara,

Toma

et al. 2023

Preprint

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After injury, mammalian spinal cords develop scars to seal off the damaged area and prevent further injury. However, excessive scarring can hinder neural regeneration and functional recovery. These competing actions underscore the importance of developing therapeutic strategies to dynamically modulate the extent of scar formation. Previous research on scar formation has primarily focused on the role of astrocytes, but recent evidence suggests that ependymal cells also participate. Ependymal cells normally form the epithelial layer encasing the central canal, but they undergo massive proliferation and differentiation into astroglia following certain types of injury, becoming a core component of scars. However, the mechanisms regulating ependymal proliferation in vivo in both healthy and injured conditions remain unclear. Here, we uncover an intercellular kappa (κ) opioid signaling pathway that controls endogenous ependymal proliferation. Specifically, we detect expression of the κ opioid receptor, OPRK1, in a functionally under-characterized cell type called cerebrospinal fluid-contacting neurons (CSF-cNs). We also discover a neighboring cell population that express the cognate ligand, prodynorphin (PDYN). Importantly, OPRK1 activation excites CSF-cNs, and systemic administration of a κ antagonist enhances ependymal proliferation in uninjured spinal cords in a CSF-cN-dependent manner. Moreover, injecting a κ agonist reduces the proliferation induced by dorsal hemisection. Altogether, our data suggest a regulatory mechanism whereby PDYN+ cells tonically release κ opioids to stimulate CSF-cNs, which in turn suppress ependymal proliferation. This endogenous pathway provides a mechanistic basis for the potential use of κ opiates in modulating scar formation and treating spinal cord injuries.

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