Exposure to Kynurenic Acid During Adolescence Produces Memory Deficits in Adulthood

Abstract

The glia-derived molecule kynurenic acid (KYNA) is an antagonist of a7 nicotinic acetylcholine receptors and the glycine B binding site on n-methyl-d-aspartateglutamate receptors, both of which have critical roles in neural plasticity as well as learning and memory. KYNA levels are increased in the brains and cerebral spinal fluid of persons with schizophrenia, leading to the notion that changes in KYNA concentration might contribute to cognitive dysfunction associated with this disorder. Indeed, recent studies indicate that increasing endogenous KYNA concentration by administering l-kynurenine (L-KYN, the precursor of KYNA) impairs spatial as well as contextual learning and memory in adult rats. In the present study, rats were treated with L-KYN (100 mg/ kg) throughout adolescence to increase endogenous KYNA concentration during this critical time in brain development. Rats were then tested drug-free as adults to test the hypothesis that exposure to elevated levels of KYNA during development may contribute to cognitive dysfunction later in life. Consistent with prior studies in which adult rats were treated acutely with L-KYN, juvenile rats exposed to increased KYNA concentration during adolescence exhibited deficits in contextual fear memory, but cue-specific fear memory was not impaired. In addition, rats treated with L-KYN as adolescents were impaired on a novel object recognition memory task when tested as adults. The memory deficits could not be explained by drug-induced changes in locomotor activity or shock sensitivity. Together, these findings add to the growing literature supporting the notion that exposure to increased concentration of KYNA may contribute to cognitive deficits typically observed in schizophrenia.

The effect of transient increases in kynurenic acid and quinolinic acid levels early in life on behavior in adulthood: Implications for schizophrenia

“…This dose of kynurenine results in a 2-3 fold increase in KYNA concentration in juvenile and adult rats (Akagbosu et al, 2012; Erhardt et al, 2004), mirroring the magnitude of the increase observed in schizophrenia (Erhardt et al, 2001; Schwarcz et al, 2001). Using kynurenine to manipulate KYNA concentration also has high translational value since an increase in kynurenine level is a primary factor leading to the increased KYNA concentration associated with schizophrenia (Miller et al, 2006; Linderholm et al, 2012).…”

“…Consistent with this hypothesis, recent studies have shown that treating rats with kynurenine throughout adolescence (PND 27-53) increases KYNA levels during the treatment period, and produces memory deficits and decreased social behavior when rats are tested as adults, despite having normal KYNA levels at the time of behavioral testing (Akagbosu et al, 2012; Trecartin & Bucci, 2011). Similarly, treating rat dams with kynurenine-enriched food from gestational day 15 to PND 21 increased KYNA concentration in the offspring, which later exhibited impaired attention and memory as adults (Alexander et al, 2013; Pocivavsek et al, 2012).…”

“…Although these data suggest that a viral-induced increase in KYNA concentration may not be sufficient to impact behavior in adults with normal immune functioning, there are several unresolved questions. For example, the studies by Asp and colleagues (2009, 2010) were conducted in mice while most other studies of developmental KYNA exposure and behavior have been carried out in rats (Akagbosu et al, 2012; Trecartin & Bucci, 2011; Alexander et al, 2013; Pocivavsek et al, 2012), making it difficult to draw firm conclusions because of potential species differences as well as strain-specific differences in behavior in mice (e.g., Falls et al, 1997). In addition, not all of the cognitive and behavioral symptoms of schizophrenia are modulated by KYNA exposure, and the effects have also been shown to depend on age of treatment (Akagbosu et al, 2012; Chess et al, 2009; Trecartin and Bucci, 2011).…”

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

“…Sequential systemic injections of kynurenine from PND 7 to 16 in mice (Liu et al, 2014) or PND 7 to 10 in rats (Iaccarino et al, 2013) result in enhanced amphetamine-induced locomotor activity and deficits in social interaction, respectively. Intermittent treatment of adolescent rats with systemic injections of kynurenine results in impaired hippocampal-mediated cognition, assessed by novel object recognition and contextual fear memory, as well as dysfunctional social interaction in adulthood (PND 61) (Akagbosu et al, 2012; Trecartin and Bucci, 2011). Importantly, this intermittent adolescent kynurenine treatment paradigm results in dysfunctional LTP after a burst of high-frequency stimulation (DeAngeli et al, 2014).…”

A systemically-available kynurenine aminotransferase II (KAT II) inhibitor restores nicotine-evoked glutamatergic activity in the cortex of rats

“…The detrimental consequences of elevated KYNA levels on glutamatergic neurotransmission and cognitive and behavioral processes have been widely demonstrated in animals with elevated brain KYNA levels, produced by administration of the precursor, L-kynurenine (KYN; Akagbosu et al, 2010; Alexander et al, 2013; Chess et al, 2007, 2009; Trecartin and Bucci, 2011; Konradsson-Geuken et al, 2010). These findings have suggested that drugs that reduce brain KYNA levels may benefit cognitive function in a wide range of patient groups (e.g., Wonodi and Schwarcz, 2010).…”