Kynurenic acid promotes activity-dependent synaptic pruning in schizophrenia

Abstract

Schizophrenia is a neurodevelopmental disorder characterized by an excessive loss of synapses. Recent data suggest that this is due to increased microglia-mediated synaptic pruning. Here, we utilize human induced pluripotent stem cell-derived models to show that kynurenic acid (KYNA), an endogenous NMDA-receptor antagonist observed to be increased in the brains of individuals with schizophrenia, reduces neuronal activity and promote microglial uptake of synapses. In a human brain organoid model, we confirm reduced microglia-mediated synaptic pruning upon inhibiting the endogenous KYNA production. To verify our experimental data in a clinical context, we integrate large-scale transcriptomic and genetic datasets and show that KYNA-producing kynurenine aminotransferases (KATs) enrich for genes governing synaptic activity and genetic risk variants for schizophrenia. Together, these results link genetic risk variants for schizophrenia to elevated production of KYNA and excessive activity-dependent synaptic pruning, while implicating pharmacological inhibition of KATs as a strategy to avoid synapse loss in schizophrenia.