Metabotropic signaling downstream of GABAA receptors suppresses neuroinflammation in Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, in which persistent neuroinflammation has been recognized as a major pathological component. Thus, strategies aimed at suppressing neuroinflammation are particularly important for developing disease-modifying therapies in PD. In this study, we examined the role of gamma-aminobutyric acid Type A Receptors (GABA A Rs) in regulating microglial activation and neuroinflammation, and their implications for neuroprotection in a lipopolysaccharide (LPS)-induced PD model. We confirmed that stimulation of GABA A Rs markedly inhibited neuroinflammation and consequently attenuated related neurotoxicity both in vitro and in vivo. Mechanistic investigations revealed that metabotropic signaling cascades downstream of GABA A Rs in microglia were involved, including intracellular calcium release and the mobilization of phosphatases, which dephosphorylated IκBα and restricted nuclear translocation of p65, thereby exerting anti-inflammatory effects. Moreover, pharmacological and immunoprecipitation assays showed that phospholipase C (PLC) physically interacted with GABA A Rs and mediated calcium release from intracellular stores. These metabotropic signaling mechanisms underlie the suppressive action of GABA A Rs on LPS-induced neuroinflammation. Given the central role of neuroinflammation in PD pathogenesis and other neurodegenerative conditions, this study provides new insights into the therapeutic potential of targeting GABA A Rs to combat neuroinflammation and neurodegeneration in PD.