TY - JOUR T1 - Reduction of Brain Kynurenic Acid Improves Cognitive Function JF - The Journal of Neuroscience JO - J. Neurosci. SP - 10592 LP - 10602 DO - 10.1523/JNEUROSCI.1107-14.2014 VL - 34 IS - 32 AU - Rouba Kozak AU - Brian M. Campbell AU - Christine A. Strick AU - Weldon Horner AU - William E. Hoffmann AU - Tamas Kiss AU - Douglas S. Chapin AU - Dina McGinnis AU - Amanda L. Abbott AU - Brooke M. Roberts AU - Kari Fonseca AU - Victor Guanowsky AU - Damon A. Young AU - Patricia A. Seymour AU - Amy Dounay AU - Mihaly Hajos AU - Graham V. Williams AU - Stacy A. Castner Y1 - 2014/08/06 UR - http://www.jneurosci.org/content/34/32/10592.abstract N2 - The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the α7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia. ER -