Upregulation of CCK3R leading to the suppression of chronic seizures

Epilepsy is a chronic neurological disorder characterized by recurrent seizures that affect millions globally. Despite the availability of various antiepileptic drugs, 30–40% of patients remain drug-resistant and continue to experience seizures. This unmet need has driven the search for novel therapies, including gene therapy. This study aimed to explore G protein-coupled receptor 173 (GPR173), also referred to as cholecystokinin receptor 3, as a gene therapy strategy for epilepsy. Previous research suggests that the upregulation of GPR173 might benefit epilepsy treatment by modulating the gamma-aminobutyric acid cholecystokinin signaling pathway involved in inducing inhibitory long-term potentiation. In a mouse model of kainic acid-induced epilepsy, GPR173 overexpression, controlled by either the cytomegalovirus or calcium/calmodulin-dependent protein kinase II promoter, significantly reduced spontaneous seizures in chronic epileptic mice. Notably, specific upregulation of GPR173 in excitatory neurons led to a more pronounced seizure reduction than in controls. Importantly, this gene therapy does not appear to cause severe adverse effects on physiological functions such as locomotor activity, anxiety, and spatial memory. However, the overexpression of GPR173 may affect the appetite of animals, thereby slowing down normal weight gain. Overall, these findings highlight the therapeutic potential of GPR173 in seizure suppression and suggest it as a new promising candidate target for epilepsy treatment. © The Author(s) 2025.