554. Kynurenic acid and promotion of activity-dependent synapse elimination in schizophrenia

Abstract

Abstract Background Schizophrenia is associated with alterations in synaptic connectivity and brain signaling, which are thought to contribute to the disorder’s core cognitive and clinical features. A growing body of evidence implicates dysregulation of tryptophan metabolism along the kynurenine pathway in schizophrenia. Within this pathway, kynurenic acid (KYNA), a neuroactive metabolite modulating glutamatergic and cholinergic neurotransmission, is consistently found at elevated levels in the central nervous system of affected individuals. However, how KYNA release is regulated in human brain models, and how altered KYNA dynamics relate to synaptic abnormalities, requires further investigation. Aims & Objectives To investigate KYNA regulation in human cellular models of schizophrenia and to explore its possible contribution to synaptic dysfunction. Method Three independent experimental approaches were used to examine the role of KYNA in schizophrenia. First, patient-derived neuronal and microglial models were used to assess the impact of KYNA on activity-dependent synaptic uptake. Second, dorsal brain organoids derived from individuals with schizophrenia and matched controls were analyzed for spontaneous release of kynurenine pathway metabolites, including KYNA, and for expression of pathway-related genes using bulk RNA sequencing. Third, dorsal brain organoids were exposed to pro-inflammatory cytokines (IFN-γ and IL-1β) to examine the effect of immune signaling on KYNA production, and kynurenine aminotransferases (KAT) inhibition was applied to reduce KYNA release. Results (i) In neuronal and microglial models, elevated KYNA promoted activity-dependent microglial uptake of synaptic structures. (ii) Patient-derived brain organoids exhibited stable, spontaneous release of kynurenine pathway metabolites, with schizophrenia-derived organoids showing differential expression of pathway-related genes. (iii) In brain organoids, pro-inflammatory cytokines (IFN-γ and IL-1β) increased KYNA release, which was attenuated by pharmacological inhibition of KATs. Discussion & Conclusions These findings link KYNA to excessive, activity-dependent synaptic elimination in human cellular models of schizophrenia and show that its dynamics are sensitive to immune signaling. This platform enables mechanistic studies of KYNA, including manipulation of its release, and suggests that KAT inhibition may help preserve synapses.