Epilepsy is a chronic
neurological disorder featuring recurrent, unprovoked
seizures, which affect more than 65 million people worldwide. Here, we discover that the PKHD1L1, which is encoded by
polycystic kidney and hepatic disease1-like 1 (Pkhd1l1), wildly distributes in neurons in the central nervous system (CNS) of mice. Disruption of PKHD1L1 in the dentate gyrus region of the hippocampus leads to increased susceptibility to
pentylenetetrazol-induced
seizures in mice. The disturbance of PKHD1L1 leads to the overactivation of the
mitogen-activated protein kinase (MAPK)/extracellular regulated
kinase (ERK)-
Calpain pathway, which is accompanied by remarkable degradation of cytoplasmic
potassium chloride co-transporter 2 (KCC2) level together with the impaired expression and function of membrane KCC2. However, the reduction of membrane KCC2 is associated with the damaged inhibitory ability of the vital
GABA receptors, which ultimately leads to the significantly increased susceptibility to epileptic
seizures. Our data, thus, indicate for the first time that Pkhd1l1, a newly discovered
polycystic kidney disease (PKD) association gene, is required in neurons to maintain neuronal excitability by regulation of KCC2 expression in CNS. A new mechanism of the clinical association between genetic PKD and
seizures has been built, which could be a potential therapeutic target for treating PKD-related
seizures.