Early developmental elevations of brain kynurenic acid impair cognitive flexibility in adults: Reversal with galantamine

Abstract

Levels of kynurenic acid (KYNA), an endogenous α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, are elevated in the brain of patients with schizophrenia (SZ) and might contribute to the pathophysiology and cognitive deficits seen in the disorder. As developmental vulnerabilities contribute to the etiology of SZ, we determined, in rats, the effects of perinatal increases in KYNA on brain chemistry and cognitive flexibility. KYNA’s bioprecursor L-kynurenine (100 mg/day) was fed to dams from gestational day 15 (GD15) to postnatal day 21 (PD21). Offspring were then given regular chow until adulthood. Control rats received unadulterated mash. Brain tissue levels of KYNA were measured at PD2 and PD21, and extracellular levels of KYNA and glutamate were determined by microdialysis in the prefrontal cortex in adulthood (PD56-80). In other adult rats, the effects of perinatal L-kynurenine administration on cognitive flexibility were assessed using an attentional set-shifting task. L-Kynurenine treatment raised forebrain KYNA levels ~3-fold at PD2 and ~2.5-fold at PD21. At PD56-80, extracellular prefrontal KYNA levels were moderately but significantly elevated (+12%), whereas extracellular glutamate levels were not different from controls. Set-shifting was selectively impaired by perinatal exposure to L-kynurenine, as treated rats acquired the discrimination and intra-dimensional shift at the same rate as controls, yet exhibited marked deficits in the initial reversal and extra-dimensional shift. Acute administration of the α7nAChR positive modulator galantamine (3.0 mg/kg, i.p.) restored performance to control levels. These results validate early developmental exposure to L-kynurenine as a novel, naturalistic animal model for studying cognitive deficits in SZ.

Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats

“…The efficacy of galantamine in this model is consistent with studies demonstrating that this drug (at a dose of 3 mg/kg) reversed set-shifting deficits in a rat model of schizophrenia based on the acute (Alexander et al, 2012) and early developmental (Alexander et al, 2013) elevation of brain kynurenic acid. Based on the assumption that the detrimental effects of kynurenic acid are purportedly mediated through the negative modulation of α7-nAChRs (Lopes et al, 2007), these authors concluded that the reinstatement of ASST performance via galantamine reflects the positive modulation of α7-nAChR.…”

Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats

“…from PD 42 to PD 49. As in our previous studies (Alexander et al 2013; Pocivavsek et al 2012), KYNA levels were increased by lacing rodent chow daily with kynurenine. Our results provide evidence that prenatal KYNA elevation alone is sufficient to induce behavioral dysfunctions later in life, and that essentially identical increases in brain KYNA during adolescence do not induce delayed deficits in hippocampus-mediated cognitive behaviors.…”

Influence of kynurenine 3-monooxygenase (KMO) gene polymorphism on cognitive function in schizophrenia

“…While there was some variability in the extent of impairment across cognitive measures, the rs2275163C>T CC group performed more poorly (arithmetically) on each and every measure. These findings are consistent with our original report and preclinical data that demonstrate impairments in spatial working memory (Chess et al, 2007) and cognitive flexibility (Pocivavsek et al, 2012, Alexander et al, 2013) in rodents following experimental manipulation of KMO function. Of note however, two of three measures that did not differ significantly as a function of genotype in our sample (effect sizes of −.14 and −.25) were both measures of verbal memory, raising the possibility that this particular cognitive function may be less sensitive to KMO variation.…”