Neuropsychopharmacology (2013) 38, S108–S272 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Monday, December 09, 2013 rats, 3 litters). To determine brain KYNA levels at those sametime points, forebrain or PFC tissue homogenates were analyzed from those sameanimals. Cortical excitability: M2. Elevations of Brain Kynurenic Acid in Prenatal Densities of apical and basal dendritic spines (expressedas Rats Result in Long-lasting Impairments in Cortical spines per 10 mm) werecalculated using Golgi-impregnated Development and Cognitive Flexibility: Implications for pyramidal neurons from the prelimbic/infralimbiccortex Schizophrenia (layer II/III; EKyn ¼ 6 pups, 4 litters; ECon ¼ 7 pups, 4 John P. Bruno*, Sarah Vunck, Michelle Pershing, litters). 4–5 neurons per animal, and 3–5 segments per Ana Pocivavsek, Dave Bortz, Christinna Jorgensen, neuron were analyzed. RTqPCR: Expressionlevels of Peter Fredericks, Benedetta Leuner, Robert Schwarcz mGluR2 mRNA were determined in brain homogenates at GD21 (EKyn ¼ 6pups, 3 litters: ECon ¼ 8 pups, 4 litters), The Ohio State University, Columbus, Ohio PD2 (EKyn ¼ 8 pups, 6 litters: ECon ¼ 12pups, 6 litters), and PD56 (EKyn ¼ 4 rats, 2 litters: ECon ¼ 3 rats, 1 litter). Background: Schizophrenia (SZ) is a debilitating psychia- Evokedglutamate release: The mesolimbic stimulation of tric disorder that presents with cognitive deficits in thought prefrontal glutamatewas quantified using a glutamate- processing, attention and working memory. Though cogni- sensitive amperometric microelectrode arrayfollowing in- tive deficits are considered core symptoms and are tra-nucleus accumbens infusions of NMDA (0.05–0.30 mg/ predictive of functional outcome, they remain largely 0.5mL)(EKyn ¼ 5 pups, 4 litters; ECon ¼ 7 pups, 5 litters). unresolved by current drug and behavioral interventions. Set Shifting Behavior: Cognitiveflexibility was assessed Thus, continued study of validated animal models may between PD56-80 using an attentional set-shifting tas- provide a platform for revealing more efficacious cognition- k(ASST) (EKyn ¼ 8 pups, 5 litters; ECon ¼ 7 pups, 4 litters). enhancing medications. Elevated kynurenic acid (KYNA) Results: KYNA levels: Compared to controls, serum levels in the brain of patients with SZ may contribute to kynurenine was increased in EKyn dams and offspring on these cognitive impairments through KYNA’s negative GD21 (dams ¼ 2223%, fetuses ¼ 692%) but not on PD2. allosteric modulation of a7 nicotinic acetylcholine receptors EKyn rats had elevated brain KYNA levels, relative to ECon, (a7*nAChRs) and subsequent reductions in extracellular on GD21 (400%) and PD56 (150%). Cortical excitability: cortical ACh and glutamate levels. This hypothesis has Relative to ECon, EKyn rats showed reductions in apical (by prompted the use of experimental elevations in brain 11%) and basal (by 14%) dendritic spine density of KYNA, at different stages of the life span, as a model of pyramidal neurons in layer II/III of the prelimbic/infra- SZ. We have reported that administration of KYNA’s limbic cortex as well as reduced expression of mRNA for bioprecursor (kynurenine) from gestational day (GD) 15 mGluR2 in frontal cortex at GD21 (by 28%) and PD56 (by through weaning produces deficits in hippocampal- and 27%). Evoked glutamate release: The mesolimbic activation prefrontal-mediated tasks when offspring are tested as of prefrontal glutamate release following intra-accumbens adults. In the present experiments, we further delineated the infusion of NMDA seen in ECon rats (3.58±0.40 mM sensitive period by elevating brain KYNA in fetuses during increase after 0.15 mg NMDA) was nearly eliminated the last prenatal week (GD15-22). Given the role of (0.43±0.22 mM) in Ekyn rats. Set Shifting Behavior: In a7nAChR activity in the development of excitatory synapses adulthood, EKyn rats exhibited deficits in the ASST at the and ultimately in the mediation of cognitive flexibility via first reversal (twice as many trials to criteria) and extra- prefrontal cholinergic and glutamatergic transmission, we dimensional shift (58% more trials to criteria) stages. determined the impact of prenatal elevations of KYNA on Conclusions: Consistent with the role of a7nAChRs on several indices of cortical excitability, including the density neuronal development, prenatal elevation of the negative of dendritic spines on cortical pyramidal neurons (layers II/ modulator KYNA in the last week of gestation produces III), the expression of mGluR2 mRNA, and evoked long lasting neuronal changes that are associated with glutamate release in prefrontal cortex (PFC). deficits in cortical excitability and cognition as adults. Methods: Subjects: KYNA levels wereelevated chronically These changes include reductions in spine density, expres- from GD 15 through GD22, by adding KYNA precursorky- sion of mGluR2 mRNA, evoked glutamate release in PFC, nurenine (100 mg/day) daily to reconstituted powdered rat and also reduced cognitive flexibility. As each of these chow fed topregnant Wistar rats (EKyn). In thecontrol changes has been described as part of the pathology condition, mothers were fed unadulterated reconstituted accompanying SZ, these results further validate prenatally powdered ratchow (ECon) for the same time period. Post elevated KYNA levels as a valuable animal model of the parturition, dry rat chow pellets were fed to dams and disease. offspringuntil the latter were tested for neurochemical or Keywords: kynurenic acid, development, glutamate, behavioral outcomes beginningat PD56. KYNA levels: cognition, schizophrenia Serumlevels of kynurenine were measured in litter-matched Disclosures: J. Bruno, Nothing to Disclose; S. Vunck, maternal and pup samples fromGD21 (EKyn ¼ 9 pups, from Nothing to Disclose; M. Pershing, Nothing to Disclose; A. 3 litters: ECon ¼ 12 pups, 4 litters) and PD2 (EKyn ¼ 12p- Pocivavsek, Nothing to Disclose; D. Bortz, Nothing to ups, 4 litters: ECon ¼ 18 pups, 6 litters), as well as adult Disclose; C. Jorgensen, Nothing to Disclose; P. Fredericks, offspring on dayPD56 (EKyn ¼ 5 rats, 3 litters: ECon ¼ 5 Nothing to Disclose; B. Leuner, Nothing to Disclose; ACNP 52nd Annual Conference Abstracts S109 R. Schwarcz, Part 1: Research support from Mitsubishi- Following the same protocol, a second group of rats (N ¼ 8) Tanabe; Bristol-Myers-Squibb (ended 2012) and Lundbeck received 0 (vehicle), 25 or 100 mg/kg 4-ClKYN, or 4-ClKYN (will start 2013). (100 mg/kg) + GAL (3 mg/kg). Results: In both groups of rats, performance under the control condition was delay-dependent. In the KYN-treated M3. Evidence for Both an Alpha7 Nicotinic and a group, accuracy was 95, 87, and 82% at 5, 10, and 15 s, Glycine B Receptor Mediation of Working Memory in respectively. Elevation of KYNA via acute administration of the Rat KYN resulted in significant deficits in performance and, as Sarah Vunck*, Michelle Pershing, Dave Bortz, Christinna expected, the detrimental effects were largest for the higher Jorgensen, Robert Schwarcz, John P. Bruno dose and longest delays. Compared to vehicle treatment, 25 mg/kg KYN significantly reduced accuracy (by 12%) only The Ohio State University, Columbus, Ohio at the longest delay (15 s), while 100 mg/kg significantly reduced accuracy at 5 s (by 11%), 10 s (by 14%), and during Background: Cognitive deficits (attention, working memory, the 15 s delay (by 33%; dropping to chance levels). Compared and cognitive flexibility) are considered a core symptom to vehicle, acute KYN (both 25 and 100 mg/kg) produced a cluster in schizophrenia (SZ); predictive of functional out- four-fold increase (from B9toB40) in sample phase come yet not alleviated by current drug and behavioral omissions during the first 15 min of the task. The detrimental interventions. Thus, there is a need for further studies on effects of 4-ClKYN were more severe than those caused by animal models to reveal more efficacious pharmacotherapies. KYN. Vehicle treatment accuracy was 96%, 87%, and 77% at A significant contributor to cognitive impairments seen in SZ 5, 10, and 15 s. 25 mg/kg 4-ClKYN reduced accuracy (by may be the elevated levels of kynurenic acid (KYNA), 33%) at the 15 s delay, while 100 mg/kg 4-ClKYN significantly observed in the brains of patients with SZ. KYNA is an reduced accuracy overall (by 60%) as well as at all delays, endogenous, astrocyte-derived metabolite that negatively well below chance performance, 5 s (by 54%), 10 s (by 60%), modulates a7 nicotinic acetylcholine receptors (a7nAChRs) and 15 s delays (by 70%). There was no significant increase at physiological concentrations and, at higher concentrations, in omissions following acute administration of 4-ClKYN. blocks the glycineB site of the NMDA receptor. We have Notably, the deficits following acute administration of reported that acute administration of KYNA’s bioprecursor L- 100 mg/kg KYN were fully prevented by co-administration kynurenine (KYN; 100 mg/kg) in intact adult rats increases of GAL. In contrast, the deficits following 100 mg/kg extracellular KYNA (B1,500%), decreases extracellular gluta- 4-ClKYNA were unaffected by treatment with GAL. mate (GLU) levels (B30%) in the prefrontal cortex (PFC), and Conclusions: Collectively, these findings suggest a role for behaviorally results in an impairment of the prefrontally- both a7nAChRs and NMDA receptors in the mediation of mediated attentional set shifting task. We investigated three working memory. Acute elevation of KYNA in adult rats issues: