Levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha 7 nicotinic acetylcholine (±7nACh) and antagonist at glutamatergic N-methyl-D-aspartate (NMDA) receptors, are elevated in the brain of patients with schizophrenia (SZ). In rats, dietary exposure to KYNA’s immediate precursor kynurenine during the last week of gestation produces neurochemical and cognitive deficits in adulthood that resemble those seen in patients with SZ. The present experiments examined whether prenatal kynurenine exposure results in age-dependent changes in the kynurenine pathway (KP), expression of selected receptors, and cognitive function. Pregnant dams were fed unadulterated mash (progeny = ECON) or mash containing kynurenine (100 mg/day; progeny = EKYN) from embryonic day (ED) 15 to 22. Male offspring were assessed as juveniles, i.e. prior to puberty (postnatal day [PD] 32), or as adults (PD70) for brain KYNA levels, ±7nACh and NMDA receptor gene expression, and performance on a trace fear conditioning (TFC) task. KYNA levels were comparable between juvenile ECON and EKYN rats whereas EKYN adults exhibited a ~3-fold increase in brain KYNA relative to ECONs. NR2A expression was persistently reduced (30–40%) in EKYN rats at both ages. Compared to ECON adults, there was a 50% reduction in NR1, and a trend toward decreased ±7nACh expression, in adult EKYN rats. Surprisingly, juvenile EKYN rats performed significantly better in the TFC paradigm than controls, whereas adult EKYN animals showed the predicted deficits. Collectively, our results provide evidence that elevated KYNA in the fetal brain alters neuronal development and causes age-dependent effects on neurochemistry and cognitive performance.

Background: Amyloid-β (Aβ) peptides derive from the amyloid precursor protein (APP) and play a pivotal role in Alzheimer's disease (AD) pathogenesis. Our previous work showed that the APP intracellular domain (AICD), which is produced simultaneously with Aβ, also contributes to the development of AD-like features. Studies show that administration of apolipoprotein E (apoE) and apoE-derived small peptide mimetics protect AD mouse models against these AD-like features. However, the effects of apoE-mimetic treatment on AICD-mediated AD-like pathologies remain to be elucidated. Objective: To study the effects of an apoE mimetic (COG112) on neuroinflammation, hyperphosphorylation of tau and defects in adult neurogenesis in AICD- overexpressing transgenic mice (FeCγ25 line). Methods: Beginning at 1 month of age, animals were administered subcutaneous COG112 3 times per week for 3 months, followed by immunohistochemical analysis for neuroinflammation, neurogenesis and phosphorylated tau. Results: Treatment with COG112 significantly reduced neuroinflammation in AICD mice and protected against impaired adult hippocampal neurogenesis. We also found that COG112 treatment reduced hyperphosphorylation and somatodendritic accumulation of tau in the hippocampus and cerebral cortex of AICD mice. Conclusions: Reduction of neuroinflammation by the apoE-mimetic COG112 protects against impaired neurogenesis and tau pathology in AICD transgenic mice. These data suggest that neuroinflammation plays an important role in AICD-induced AD-like pathologies.

Rationale-Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating brain levels of kynurenic acid (KYNA). KYNA's effects may reflect interference with the function of both the a7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor. Objectives-The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP). Methods-DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Clkynurenic acid). Attenuation of KYN-or 4-Cl-KYN-induced deficits was assessed by coadministration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of a7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site. Results-Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were