AbstractAimsSemaphorin7A (Sema7A) plays an important role in the immunoregulation of the brain. In our study, we aimed to investigate the expression patterns of Sema7A in epilepsy and further explore the roles of Sema7A in the regulation of seizure activity and the inflammatory response in PTZ‐kindled epileptic rats.MethodsFirst, we measured the Sema7A expression levels in patients with temporal lobe epilepsy (TLE) and in rats of a PTZ‐kindled epilepsy rat model. Second, to explore the role of Sema7A in the regulation of seizure activity, we conducted epilepsy‐related behavioral experiments after knockdown and overexpression of Sema7A in the rat hippocampal dentate gyrus (DG). Possible Sema7A‐related brain immune regulators (eg, ERK phosphorylation, IL‐6, and TNF‐α) were also investigated. Additionally, the growth of mossy fibers was visualized by anterograde tracing using injections of biotinylated dextran amine (BDA) into the DG region.ResultsSema7A expression was markedly upregulated in the brain tissues of TLE patients and rats of the epileptic model after PTZ kindling. After knockdown of Sema7A, seizure activity was suppressed based on the latency to the first epileptic seizure, number of seizures, and duration of seizures. Conversely, overexpression of Sema7A promoted seizures. Overexpression of Sema7A increased the expression levels of the inflammatory cytokines, IL‐6 and TNF‐α, ERK phosphorylation, and growth of mossy fibers in PTZ‐kindled epileptic rats.ConclusionSema7A is upregulated in the epileptic brain and plays a potential role in the regulation of seizure activity in PTZ‐kindled epileptic rats, which may be related to neuroinflammation. Sema7A promotes the inflammatory cytokines TNF‐α and IL‐6 as well as the growth of mossy fibers through the ERK pathway, suggesting that Sema7A may promote seizures by increasing neuroinflammation and activating pathological neural circuits. Sema7A plays a critical role in epilepsy and could be a potential therapeutic target for this neurological disorder.