Prenatal kynurenine exposure in rats: age-dependent changes in NMDA receptor expression and conditioned fear responding

Abstract

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.

Preferential Disruption of Prefrontal GABAergic Function by Nanomolar Concentrations of the α7nACh Negative Modulator Kynurenic Acid

“…Therefore, it is possible that persistent elevations of KYNA in the PFC during adolescence may elicit enduring GABAergic dysfunction and disrupt the acquisition of inhibitory control that normally emerges in the adult PFC (Caballero et al, 2016). Elevations of KYNA levels during sensitive periods of perinatal development Alexander et al, 2013;Forrest et al, 2013;Liu et al, 2014;Pisar et al, 2014;Pershing et al, 2015Pershing et al, , 2016 or adolescence (Akagbosu et al, 2012;DeAngeli et al, 2014, Pershing et al, 2016 may alter the balance of E-I in the PFC and contribute to the onset of cognitive deficits later in life, as seen in schizophrenia and other major psychiatric disorders.…”

“…Of special interest in this context is the abnormal elevation of the tryptophan metabolite kynurenic acid (KYNA) in the PFC of individuals with schizophrenia, a biochemical dysregulation that is not secondary to antipsychotic medication Ceresoli-Borroni et al, 2006;Larsson et al, 2015). Brain KYNA is an astrocyte-derived metabolite that is present in the mammalian CNS at nanomolar concentrations (Moroni et al, 1988;Turski et al, 1988) and negatively modulates ␣7-nicotinic acetylcholine receptor (␣7nAChR) function under physiological conditions (Albuquerque and Schwarcz, 2013).…”

“…Brain KYNA is an astrocyte-derived metabolite that is present in the mammalian CNS at nanomolar concentrations (Moroni et al, 1988;Turski et al, 1988) and negatively modulates ␣7-nicotinic acetylcholine receptor (␣7nAChR) function under physiological conditions (Albuquerque and Schwarcz, 2013). At higher concentrations, KYNA can also function as a competitive inhibitor of the glycine coagonist (glycine-B) site of the NMDA receptor (NMDAR) (Kessler et al, 1989;Parsons et al, 1997).…”

Oral administration of a specific kynurenic acid synthesis (KAT II) inhibitor attenuates evoked glutamate release in rat prefrontal cortex

“…Notably, elevations in KYNA during sensitive periods of late gestation, have also been shown to reduce the gain of GABAergic transmission that occurs post-adolescence in the maturing PFC (Thomases et al, SFN 2014). In line with these neurochemical and electrophysiological effects, acute elevation of KYNA levels in adults, or chronic elevations of KYNA during sensitive periods of development, causes cognitive deficits that resemble those seen in persons with SZ, including diminished cognitive flexibility (Alexander et al, 2012; Alexander et al, 2013; Pershing et al, 2015), trace fear conditioning (Pershing et al, 2016), spatial working memory, and conditioned avoidance tasks (Pocivavsek et al, 2012). …”

Kynurenine Pathway as a New Target of Cognitive Impairment Induced by Lead Toxicity During the Lactation

“…Specifically, kynurenic acid (KYNA) has been involved in brain development 17 and cognitive process 18 since it is the unique endogenous antagonist of NMDA receptor and a negative allosteric modulator of alpha7-nicotinic receptors. It has been suggested that the high KYNA levels found in fetal brain as well as its rapid decline during the postnatal period, are involved in NMDAr modulation, necessary for the normal brain development 19,20 . In this context, it has been shown that the fluctuation in brain KYNA levels can cause impairment in working memory, sensorimotor gating and in the attention process in adult rodents [21][22][23] .Numerous publications have recently demonstrated that both Pb 2+ exposure as well as KYNA levels fluctuation during the pre-and postnatal period, lead to cognitive impairment.…”