GABA Receptor-Mediated Effects in the Peripheral Nervous System: A Cross-Interaction With Neuroactive Steroids

Abstract

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult mammalian central nervous system (CNS), exerts its action via an interaction with specific receptors (e.g., GABAA and GABAB). These receptors are expressed not only in neurons but also on glial cells of the CNS, which might represent a target for the allosteric action of neuroactive steroids. Herein, we have demonstrated first that in the peripheral nervous system (PNS), the sciatic nerve and myelin-producing Schwann cells express both GABAA and GABAB receptors. Specific ligands, muscimol and baclofen, respectively, control Schwann-cell proliferation and expression of some specific myelin proteins (i.e., glycoprotein P0 and peripheral myelin protein 22 [PMP22]). Moreover, the progesterone (P) metabolite allopregnanolone, acting via the GABAA receptor, can influence PMP22 synthesis. In addition, we demonstrate that P, dihydroprogesterone, and allopregnanolone influence the expression of GABAB subunits in Schwann cells. The results suggest, at least in the myelinating cells of the PNS, a cross-interaction within the GABAergic receptor system, via GABAA and GABAB receptors and neuroactive steroids.

Neurosteroid regulation of central nervous system development

“…In addition, progesterone increased expression of its receptor and of myelin proteins in co-cultured dorsal root ganglial neurons, but did not increase expression or nuclear localization of the progesterone receptor in Schwann cells . Neither progesterone nor RU-486 affected expression of progesterone receptor mRNA in Schwann cell cultures, suggesting that effects of progesterone on Schwann cells may be mediated through other receptors, or may be mediated through metabolism to other neurosteroids such as allopregnanolone (Magnaghi et al, 2006;Magnaghi et al, 2001). Thus, progesterone affects myelin synthesis directly in Schwann cells as well as indirectly through induction of gene expression in neurons.…”

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

“…Gupta and colleagues (78) presented data that the neuroactive steroids progesterone and allopregnanolone were decreased in the brains of SSADH-deficient mice. GABA synthesis may be activated by neurosteroids, especially allopregnanolone (116,117), and GABA(B) receptors (downregulated in SSADH-deficient micesee below) can influence the levels of myelin-associated proteins (115). Accordingly, the myelin effects observed in the mutant mice are likely a culmination of many processes, involving GABA levels, GABAergic receptors and neuroactive steroid levels (Fig.…”

GABA and Neuroactive Steroid Interactions in Glia: New Roles for Old Players?

“…astrocytes and activated microglia) exhibit GABA-B receptor immunoreactivity [43,94] and might be considered also a target for the action of GABA-B receptor modulators [47,116,126]. Furthermore, since functionally active GABA-A and GABA-B receptors are present in the Schwann cells of the PNS [149,151,169], it indicates that also these peripheral glial cells are a target for GABA ligands and neuroactive steroids. Additionally, also the glial precursor O-2A cells express GABA-A receptors [251,259].…”

“…• Rat sciatic nerve; in particular 2, 3, 1-3 subunits [149,151,169] • Culture from rat sciatic nerve; in particular 2,…”

“…GABA-A receptors are present on normal mammalian sensory axons and are re-established on regenerated sensory axons [24], although the presence of these receptors on Schwann cells has not been further investigated in detail. Recent studies performed in our laboratory using RT-PCR and immunohistochemistry, demonstrated that Schwann cells in culture express several subunits of the GABA-A receptor, such as the 2, 3, 1-3 subunits [149,151,169] ( Table 1). The presence of GABA-B receptor in the PNS, has been previously demonstrated in the rat DRG, in peripheral axons, in autonomic nerve terminals and in pig nodose ganglion cells [28,51,142,239,242,262], although its cellular localization has never been considered.…”