434. The effect of kynurenic acid (KYNA) release on glutamatergic transmission in the hippocampus - a model of schizophrenia

Abstract

Abstract Background Schizophrenia is a psychiatric disorder that has debilitating symptomatic manifestations, including psychotic episodes, depression-like symptoms, as well as cognitive dysfunction, all three of which contribute to the heavy disease burden for the individual. Multiple hypotheses have been developed in hope of understanding the dysfunctional neurotransmission underlying schizophrenia. Among them is the hippocampal hyperactivity model of schizophrenia, which proposes an imbalance in excitatory and inhibitory transmission in the hippocampus, causing an acute increase in glutamatergic transmission that eventually shift into excitotoxicity and the degeneration of the hippocampus in an early phase of the disease. Kynurenic acid (KYNA) is a neuroactive metabolite of the kynurenic pathway that has been identified as a possible initiator of schizophrenia pathophysiology. Pharmaceutical NMDA receptor- antagonists, such as phencyclidine (PCP), have the ability to induce psychotic and cognitive symptoms similar to the ones seen in schizophrenia patients. As an endogenous NMDA receptor- antagonist, KYNA may have the ability to replicate the effect on glutamatergic transmission that leads to the emergence of above-mentioned symptoms. It was hypothesized that KYNA contributes to the dysregulation in glutamatergic transmission that is observed in schizophrenia pathophysiology, and that the administration of an inhibitor of KYNA synthesis has the ability to possibly reverse pathophysiology. Aims & Objectives The aim of this study was to investigate the effect of stimulated KYNA synthesis on glutamatergic transmission in the hippocampus of Sprague Dawley rats. The study also aimed to investigate the effect of inhibiting KYNA production on glutamatergic transmission in the hippocampus following KYN stimulation. Method Electrophysiological techniques extracellular recording as well as calcium-imaging were used in this study. Results The results show that stimulating KYNA synthesis in hippocampal slices increases the level of glutamate release in the CA1 region of the hippocampus, and facilitated NMDA-mediated transmission in both the CA1 and CA3 regions of the hippocampus. The inhibition of KYNA production removed the facilitation effect of KYN on NMDA-mediated transmission at certain concentrations. Discussion & Conclusions Thus, the kynurenic pathway and its neuroactive metabolites pose an attractive potential target for future pharmaceutical treatment and improved clinical management of schizophrenia.