FPR2 contributes to the dysfunction of inflammation resolution and neuronal excitability in focal cortical dysplasia type IIb and tuberous sclerosis complex

Abstract Background Focal cortical dysplasia IIb (FCDIIb) and tuberous sclerosis complex (TSC) show the persistent neuroinflammation which promote epileptogenesis and epilepsy progression, suggesting that endogenous resolution of inflammation is inadequate to relieve neuronal network hyperexcitability. To explore the potential roles of formyl peptide receptor 2 (FPR2), which is a key regulator of inflammation resolution, in epilepsy in FCDIIb and TSC. We examined the expression and cellular distribution of FPR2, and the effect of FPR2 signal pathway on the neuronal excitability. Method The expression of FPR2 and NF-κB signal pathway were examined by real-time PCR, western blots and analyzed via one-way analysis of variance (ANOVA). The distribution of FPR2 was detected using immunostaining. The expression of resolvin D1(RvD1, the endogenous ligand of FPR2)was observed via ELISA. The calcium imaging was used to measure intracellular calcium concentrations in FPR2-affected rat cortical neurons. The effects of FPR2 on the electrophysiological properties of neurons was detected by the Whole-cell patch clamp recording. The Pearsoncorrelation test was used to evaluate the relation between the expression of FPR2, RvD1 and clinical variants. Results The expression of FPR2 and resolvin D1 (RvD1) were significantly lower in FCDⅡb and TSC cortical lesions than the controls and was negatively correlated with seizure frequency; specially, in dysplastic neurons; but, FPR2 was sparse in microglia and nearly absent in astrocytes. Further, NF-κB pathway activity was upregulated in FCDⅡb and TSC and restricted by the RvD1-FPR2, but FPR2 antagonist, WRW4 exerted the opposite effects. Beyond that, RvD1-FPR2 reduced [Ca2+] influx of cortical neurons, but WRW4 increased intracellular [Ca2+]i. Importantly, RvD1-FPR2 also regulated the neuronal excitability through reducing the amplitude of spontaneous excitatory postsynaptic current (sEPSC) with NR2A and NR2B decrease. However, both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSC) of cortical neurons were not affected by RvD1 or WRW4 treatment. Conclusion In summary, these results suggest that the FPR2 was involved in epilepsy caused by FCDⅡb and TSC and FPR2 activation may contribute to control the epilepsy in FCDⅡb and TSC.