G Protein-Coupled Receptor 32 Contributes to Inflammation Resolution and Neuronal Excitability Dysfunction in Patients With Focal Cortical Dysplasia IIb and Tuberous Sclerosis Complex.

BACKGROUND

Focal cortical dysplasia IIb (FCDIIb) and tuberous sclerosis complex (TSC) show persistent neuroinflammation that promotes epileptogenesis and epilepsy progression, suggesting that endogenous resolution of inflammation is inadequate to relieve neuronal network hyperexcitability. G-protein-coupled receptor 32 (GPR32) is a key regulator of inflammation resolution and we aimed to explore the roles of GPR32 in cortical lesions of patients with FCDIIb and TSC.

METHOD: We examined the expression and distribution of GPR32 in patients with FCDIIb and TSC and its effects on human microglial cell activation, inflammation and the electrophysiological properties of neurons.

RESULTS

GPR32 and Resolvin D1 expression was significantly lower in cortical lesions of patients with FCDIIb and TSC than in controls and were negatively correlated with seizure frequency. GPR32 was widely distributed in neurons and microglia and was nearly absent in astrocytes. Furthermore, the Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) pathway was downregulated in patients with FCDIIb and TSC. The GPR32/SHP2/nuclear factor-kappa B pathway inhibited the M1 transformation of microglia to produce numerous pro-inflammatory mediators and promoted M2 polarisation. GPR32 also regulated neuronal excitability by reducing the amplitude and frequency of spontaneous excitatory postsynaptic currents.

CONCLUSION

Our results suggest that GPR32 may help control epilepsy in patients with FCDIIb and TSC.