GABA Receptor Agonists Protect From Excitotoxic Damage Induced by AMPA in Oligodendrocytes

Laura Bayón-Cordero; Blanca Isabel Ochoa-Bueno; Asier Ruiz; Marina Ozalla; Carlos Matute; María Victoria Sánchez-Gómez

doi:10.3389/fphar.2022.897056

GABA Receptor Agonists Protect From Excitotoxic Damage Induced by AMPA in Oligodendrocytes

Front Pharmacol. 2022 Jul 26:13:897056. doi: 10.3389/fphar.2022.897056. eCollection 2022.

Authors

Laura Bayón-Cordero^{1

2

3}, Blanca Isabel Ochoa-Bueno^{1

2

3}, Asier Ruiz^{1

2

3}, Marina Ozalla², Carlos Matute^{1

2

3}, María Victoria Sánchez-Gómez^{1

2

3}

Affiliations

¹ Laboratory of Neurobiology, Achucarro Basque Center for Neuroscience, Leioa, Spain.
² Department of Neurosciences, University of the Basque Country (UPV/EHU), Leioa, Spain.
³ Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.

Abstract

Oligodendrocytes are the myelin forming cells of the central nervous system, and their vulnerability to excitotoxicity induced by glutamate contributes to the pathogenesis of neurological disorders including brain ischemia and neurodegenerative diseases, such as multiple sclerosis. In addition to glutamate receptors, oligodendrocytes express GABA receptors (GABAR) that are involved in their survival and differentiation. The interactions between glutamate and GABAergic systems are well documented in neurons, under both physiological and pathological conditions, but this potential crosstalk in oligodendrocytes has not been studied in depth. Here, we evaluated the protective effect of GABAR agonists, baclofen (GABA_B) and muscimol (GABA_A), against AMPA-induced excitotoxicity in cultured rat oligodendrocytes. First, we observed that both baclofen and muscimol reduced cell death and caspase-3 activation after AMPA insult, proving their oligoprotective potential. Interestingly, analysis of the cell-surface expression of calcium-impermeable GluR2 subunits in oligodendrocytes revealed that GABAergic agonists significantly reverted GluR2 internalization induced by AMPA. We determined that baclofen and muscimol also impaired AMPA-induced intracellular calcium increase and subsequent mitochondrial membrane potential alteration, ROS generation, and calpain activation. However, AMPA-triggered activation of Src, Akt, JNK and CREB was not affected by baclofen or muscimol. Overall, our results suggest that GABAR activation initiates alternative molecular mechanisms that attenuate AMPA-mediated apoptotic excitotoxicity in oligodendrocytes by interfering with expression of GluR subunits in membranes and with calcium-dependent intracellular signaling pathways. Together, these findings provide evidence of GABAR agonists as potential oligodendroglial protectants in central nervous system disorders.

Keywords: AMPA; GABA receptor; baclofen; excitotoxicity; multiple sclerosis; muscimol; oligodendrocyte.