GABA synthesis in Schwann cells is induced by the neuroactive steroid allopregnanolone

Abstract

J. Neurochem. (2009) 112, 980–990. Abstract Recent evidence showed that neurotransmitters are synthesised in glial cells, such as the Schwann cells, which form myelin sheaths in the PNS. While the presence of GABA type A (GABA‐A) receptors has been previously demonstrated in these cells, the evidence of GABA synthesis remained still elusive. In an attempt to demonstrate the presence of GABA in rat Schwann cells, we adopted a strategy, using several integrated neurochemical, molecular as well as immunocytochemical approaches. We first demonstrated the presence of glutamic acid decarboxylase of 67 kDa (GAD67) in Schwann cells, a crucial enzyme of the GABA synthesis mechanism. Second, we demonstrated that GABA is synthesized and localized in Schwann cells. As the third step we showed that allopregnanolone (10 nM), a potent allosteric modulator of GABA‐A receptors, stimulates GABA synthesis through increased levels of GAD67 in Schwann cells. Analysis of intracellular signalling mechanisms revealed that the protein kinase A pathway, through enhanced cAMP levels and cAMP response element binding protein phosphorylation, modulates the allosteric action of allopregnanolone at the GABA‐A receptor in Schwann cells. Our findings are the first to demonstrate that this GABA mechanism is active in Schwann cells thus establishing new potential therapeutic targets to control Schwann cell biology, which may prove useful in the treatment of several neurodegenerative disorders.

Nerve Regenerative Effects of GABA-B Ligands in a Model of Neuropathic Pain

“…However, part of the effects achieved with CGP56433 treatment alone (for instance the nociceptive responses, the number of myelinated fibers, and the gait) may result from the blocking of GABA-B receptor activation by endogenous GABA. This is compatible with the capacity of peripheral nerves (i.e., the Schwann cells) to synthesize and release GABA [63]. Schwann cells, indeed, resulted to be particularly responsive to CGP56433, revealing a specific effect mediated by the GABA-B receptors present on their cell surfaces.…”

Peripartum neuroactive steroid and γ-aminobutyric acid profiles in women at-risk for postpartum depression

“…The differences we report in peripartum NAS concentrations could represent differential metabolism within the progesterone-based biosynthetic pathway, either peripherally and/or in the brain, though they are regulated differently (Paul and Purdy, 1992). Differences in NAS concentrations could affect further downstream interactions with glutamic acid decarboxylase (GAD), which catalyzes glutamate decarboxylation to GABA, as there is evidence that NAS can induce GABA synthesis via GAD (Magnaghi et al, 2010) and that changes in GAD mRNA expression are associated with changes in brain GABA and glutamate levels across the peripartum period (Zhao and Gammie, 2014). Additionally, there is increasing evidence that abnormalities in GABA A R neuroplasticity, changes driven by chronic NAS exposure, alter the balance of neuronal excitability and inhibition (Maguire and Mody, 2008) in animal models.…”

Levels and actions of progesterone and its metabolites in the nervous system during physiological and pathological conditions

“…Indeed, treatment with antagonist (i.e., bicuculline) or agonist (i.e., muscimol) of GABA-A receptor abolished or mimicked, respectively the stimulatory effect exerted by 3a-THP on PMP22 . 3a-THP also influences GABA pathways in Schwann cells by increasing the expression of glutamic acid decarboxylase and the consequent stimulation of GABA synthesis (Magnaghi et al, 2010). 3a-THP also increases the activity of excitatory amino acid carrier 1 and therefore, glutamate uptake (Perego et al, 2011).…”