Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy. Lowering the levels of N-methyl-D-aspartate receptor (NMDAR) ligands has been suggested as a promising therapeutic strategy for TLE. D-Serine gates synaptic NMDARs in the hippocampus but the effect of D-serine on seizure activity remains poorly understood. Here, we show that serine levels in the hippocampus were increased in persons with TLE and in a mouse model of TLE. Eliminating D-serine or blocking its binding with NMDARs suppressed seizures in mouse models. Astrocyte-derived L-serine was found to regulate interstitial D-serine levels and seizure activity through a process controlled by phosphoserine phosphatase (PSPH). We identified a potent PSPH inhibitor, Z218484536, and found that its systemic administration reduced spontaneous epileptic discharges in mouse and cynomolgus monkey models of TLE. Overall, these results indicate that PSPH is a promising therapeutic target for TLE and support further preclinical studies of Z218484536.