Downregulated GPR30 expression in the epileptogenic foci of female patients with focal cortical dysplasia type IIb and tuberous sclerosis complex is correlated with ¹⁸F‐FDG PET‐CT values

Abstract

Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) are typical causes of developmental delay and refractory epilepsy. G-protein-coupled receptor 30 (GPR30) is a specific estrogen receptor that is critical in neurodevelopment, neuroinflammation, and neuronal excitability, suggesting that it plays a potential role in the epilepsy of patients with FCDIIb and TSC. Therefore, we investigated the role of GPR30 in patients with FCDIIb and TSC. We found that the expression of GPR30 and its downstream protein kinase A (PKA) pathway were decreased and negatively correlated with seizure frequency in female patients with FCDIIb and TSC, but not in male patients. GPR30 was widely distributed in neurons, astrocytes, and microglia, and its downregulation was especially notable in microglia. The GPR30 agonist G-1 increased the expression of PKA and p-PKA in cultured cortical neurons, and the GPR30 antagonist G-15 exhibited the opposite effects of G-1. The NF-κB signaling pathway was also activated in the specimens of female patients with FCDIIb and TSC, and was regulated by G-1 and G-15 in cultured cortical neurons. We also found that GPR30 regulated cortical neuronal excitability by altering the frequency of spontaneous excitatory postsynaptic currents and the expression of NR2A/B. Further, the relationship between GPR30 and glycometabolism was evaluated by analyzing the correlations between GPR30 and 18 F-FDG PET-CT values (standardized uptake values, SUVs). Positive correlations between GPR30 and SUVs were found in female patients, but not in male patients. Intriguingly, GPR30 expression and SUVs were significantly decreased in the epileptogenic tubers of female TSC patients, and ROC curves indicated that SUVs could predict the localization of epileptogenic tubers. Taken together, our results suggest a potential protective effect of GPR30 in the epileptogenesis of female patients with FCDIIb and TSC. | 347 GPR30 EXPRESSION IN THE EPILEPTOGENIC FOCI K E Y W O R D S 18 F-FDG Positron emission tomography-computerized tomography, focal cortical dysplasia type IIb, G-protein-coupled receptor 30, standardized uptake values, tuberous sclerosis complex, whole-cell patch-clamp

Downregulated FPR2 expression in the epileptogenic foci of focal cortical dysplasia type IIb and tuberous sclerosis complex patients

“…TLR2, TLR4 and their endogenous ligand HMGB1 are highly expressed in MCDs and further activate NF-κB signaling through the TRIF pathway (Wang et al 2018). Our previous studies also showed that the NF-κB pathway was signi cantly activated in the epileptogenic foci of patients with MCDs (Wang et al 2021). These studies suggest that in ammation persists in MCDs, and active in ammatory resolution fails to extinguish this in ammation.…”

“…The mean optical density (MOD) of FPR2 was determined according to a previous report (Wang et al 2021). Brie y, the stained sections were assessed using a light microscope (BX51, Olympus, Japan).…”

“…In addition, RvD1 alleviated in ammation in trophoblasts caused by chorioamnionitis in vivo and vitro through the FPR2/NF-κB pathway). Many studies have demonstrated that NF-κB is increased in the epileptic brain and dysregulates various proin ammatory mediators, such as IL-1β, IL-6 and TNF-α(Wang et al 2021). These ndings suggest that FPR2 activation might regulate in ammatory factors and play a neuroprotective role by inhibiting the NF-κB pathway in FCDIIb and TSC patients.…”

Downregulated formyl peptide receptor 2 expression in the epileptogenic foci of patients with focal cortical dysplasia type IIb and tuberous sclerosis complex

“…The product of the intensity and frequency score was calculated as the IR score. In addition, the mean optical density (MOD) of FPR2 was calculated using the same procedure as given in a previous study 30 . The photographs and MOD were analyzed with Image‐Pro Plus software (Media Cybernetics).…”

The role of voltage-gated chloride channels in the epileptogenesis of temporal lobe epilepsy

“…Slice preparation and electrophysiological recordings were performed in a similar way to our previous study. [13] Control or TLE mice were anesthetized with phenobarbital sodium (60 mg/kg, i.p.) and the brains were rapidly decapitated, removed and placed in an ice-cold sucrose-based dissecting solution (in mM): sucrose (300), KCl (2), NaH 2 PO 4 (1.25), CaCl 2 (1), MgCl 2 (5), NaHCO 3 (26) and glucose (11).…”