Microglial GPR35 Ameliorates Epileptogenesis and Neuroinflammation via PDGFA Domain 2 Signaling

Neuroinflammation is a critical driver of epileptogenesis and cognitive dysfunction in epilepsy; however, targeted anti-inflammatory therapies remain limited. In this study, we demonstrate that microglial GPR35 orchestrates neuroinflammatory epileptic networks through platelet-derived growth factor A (PDGFA)-dependent signaling. Single-nucleus RNA Sequencing of patients with temporal lobe epilepsy (TLE) and pharmacological models reveals selective GPR35 upregulation in disease-associated microglia. GPR35 deficiency exacerbates seizure susceptibility and cognitive deficits. We further demonstrate that GPR35 activation mitigates seizures, suppresses hippocampal neuroinflammation, and alleviates cognitive deficits. Mechanistically, kynurenic acid-activated GPR35 specifically interacts with PDGFA domain 2 via defined binding motifs, thereby suppressing PDGFA degradation through the ubiquitin-proteasome pathway. This cascade triggers PI3K-AKT signaling and subsequently inhibits pro-inflammatory responses. Conversely, GPR35 deficiency disrupts this pathway of neuroinflammation, and hyperexcitability. PDGFA overexpression phenocopies GPR35 activation, attenuating inflammation and epileptogenesis. These findings establish GPR35 as a critical modulator of epileptic networks via PDGFA-dependent anti-inflammatory signaling, bridging neuroimmune crosstalk with the pathophysiology of epilepsy. Our study identifies GPR35 as a druggable target capable of disrupting the vicious cycle of inflammation and hyperexcitability in epilepsy, offering a dual therapeutic strategy to alleviate seizures and cognitive comorbidities.

GPR35; PDGFA; epileptogenesis; kynurenic acid; neuroinflammation.