Kynurenic Acid and Promotion of Activity-Dependent Synapse Elimination in Schizophrenia

Schizophrenia is a neurodevelopmental disorder characterized by an excessive loss of synapses. Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan along the kynurenine pathway, can induce schizophrenia-related phenotypes in rodents, and clinical studies have revealed elevated KYNA levels in the CNS of individuals with schizophrenia. However, the factors that cause elevated KYNA levels in schizophrenia, and the mechanisms by which KYNA contributes to pathophysiology, remain largely elusive. The authors used patient-derived cellular modeling to test the hypothesis that KYNA can induce microglia-mediated synapse engulfment by reducing neuronal activity. Patient-derived induced pluripotent stem cells were used to generate 2D cultures of neurons and microglia-like cells, as well as forebrain organoids with innately developing microglia, to study how KYNA influences synaptic activity and microglial uptake of synaptic structures. To verify the experimental data in a clinical context, large-scale developmental postmortem brain tissue and genetic datasets were used to study coexpression networks for the KYNA-producing kynurenine aminotransferases (KATs) regarding enrichment for common schizophrenia genetic risk variants and functional annotations. In these patient-derived experimental models, KYNA induced uptake of synaptic structures in microglia, and inhibition of the endogenous KYNA production led to a decrease in the internalization of synapses in microglia. The integrated large-scale transcriptomic and genetic datasets showed that KYNA-producing KATs enriched 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 and activity-dependent internalization of synaptic material in microglia, while implicating pharmacological inhibition of KATs as a strategy to avoid synapse loss in schizophrenia.