66. Broad Monitoring Deficits in Schizophrenia: Converging Evidence From a Rat Model of Prenatal Kynurenic Acid Elevation

Abstract

Abstract Background: Cognitive deficits in people with schizophrenia (PSZ) are manifold. Efforts to develop pharmacotherapy for these symptoms rely on their reduction to a finite number of underlying problems. In recent years, evidence has been accumulating that PSZ have a narrowed attentional focus, with exaggerated filtering of locations or stimuli not currently at its center. This was first suggested by results from a Posner-type paradigm with 4 possible target locations, in which signal detection benefits from a predictive cue were more pronounced in PSZ than in healthy participants. With decreasing cue precision and the need to monitor a wider array, performance deficits became incrementally more prominent in PSZ (Hahn et al. 2012, J Abnorm Psychol 121:119–128). The present study tested whether a similar deficit could be detected in rats treated prenatally with kynurenine (EKyn). The EKyn model is associated with elevated kynurenic acid, an endogenous antagonist of α7 nicotinic and NMDA receptors implicated in the pathology of schizophrenia, and with cognitive deficits reminiscent of those seen in PSZ (Pocivavsek et al. 2014, Psychopharmacology 231:2799–2809). Methods: To create EKyn rats, 100 mg of kynurenine, the bioprecursor of kynurenic acid, was added to the daily chow of pregnant Wistar dams on embryonic days 15–22. Seventeen EKyn and 19 control (ECon) rats were trained to stable performance on the 5-Choice Serial Reaction Time Task, a rat model of attention requiring the localization of a 1-s light stimulus presented randomly in one of 5 horizontally arranged apertures. The animals’ ability to spread attention broadly across the array of locations was measured by parsing performance as a function of stimulus location. Results: Throughout the 4-month training period and beyond, EKyn rats displayed robust elevations in omission errors and reduced anticipatory responding relative to ECon rats. Responding was slower in the EKyn group, but this difference diminished towards the end of the training period. After training, omission errors and stimulus-contingent responses over a 4-week period were analyzed as a function of target location. Both groups displayed less correct responding, more incorrect responding, and more omission errors with greater target eccentricity [main effects of location: F(4, 140)>10, P < .001]. The effect of stimulus eccentricity on correct responses was more pronounced in EKyn animals, as supported by a group x location interaction [F(4, 136) = 2.60, P < .04]. Specifically, EKyn rats displayed a greater tendency to neglect stimuli presented at the peripheral locations, with no group difference at the central location. Conclusion: The results are consistent with a broad monitoring deficit in EKyn rats, reminiscent of findings in people with schizophrenia. This may suggest the EKyn model as a tool for screening pharmacological remedies of this abnormality. Funding: P50 MH103222