Prenatal Kynurenine Elevation Elicits Sex-Dependent Changes in Sleep and Arousal During Adulthood: Implications for Psychotic Disorders

Abstract

Dysregulation of the kynurenine pathway (KP) of tryptophan catabolism has been implicated in psychotic disorders, including schizophrenia and bipolar disorder. Kynurenic acid (KYNA) is a KP metabolite synthesized by kynurenine aminotransferases (KATs) from its biological precursor kynurenine and acts as an endogenous antagonist of N-methyl-D-aspartate and α7-nicotinic acetylcholine receptors. Elevated KYNA levels found in postmortem brain tissue and cerebrospinal fluid of patients are hypothesized to play a key role in the etiology of cognitive symptoms observed in psychotic disorders. Sleep plays an important role in memory consolidation, and sleep disturbances are common among patients. Yet, little is known about the effect of altered KP metabolism on sleep–wake behavior. We presently utilized a well-established experimental paradigm of embryonic kynurenine (EKyn) exposure wherein pregnant dams are fed a diet laced with kynurenine the last week of gestation and hypothesized disrupted sleep–wake behavior in adult offspring. We examined sleep behavior in adult male and female offspring using electroencephalogram and electromyogram telemetry and determined sex differences in sleep and arousal in EKyn offspring. EKyn males displayed reduced rapid eye movement sleep, while female EKyn offspring were hyperaroused compared to controls. We determined that EKyn males maintain elevated brain KYNA levels, while KYNA levels were unchanged in EKyn females, yet the activity levels of KAT I and KAT II were reduced. Our findings indicate that elevated prenatal kynurenine exposure elicits sex-specific changes in sleep–wake behavior, arousal, and KP metabolism.

Time of Day-Dependent Alterations in Hippocampal Kynurenic Acid, Glutamate, and GABA in Adult Rats Exposed to Elevated Kynurenic Acid During Neurodevelopment

“…Of interest, our current focus extensively evaluated the contribution of the time of day of experimentation, while also expanding our understanding of biochemical dynamics in both sexes of EKyn offspring. Our results reinforce previous findings that the long term consequences of prenatal KYNA elevation manifest in the attenuation of glutamate levels in the rat hippocampus (21) and complement our recent characterization of sex-dependent diurnal changes in sleep and arousal behaviors in EKyn offspring (27). As no differences in weight were observed between EKyn and control offspring, we presently provide critical evidence, in both sexes, that the reported long-term manifestation of prenatal KYNA elevation are not attributed to body weight differences.…”

“…Consistent with our previous evaluation of KP metabolites in the plasma of EKyn offspring (26,27), plasma tryptophan, kynurenine, and KYNA remained unchanged between experimental groups at ZT 0 and ZT 12. Within the brain however, KYNA levels in dissected hippocampal tissue were significantly elevated in male EKyn offspring during the middle of the light phase (ZT 6), supporting our findings from previous studies evaluating brain tissue KYNA content in EKyn compared to ECon offspring (25)(26)(27)33). We presently selected the time points that correspond to transitions between the light and dark phases for rodents, as we previously studied time points that corresponded to the middle of the light and dark phases for rodents (27).…”

“…Within the brain however, KYNA levels in dissected hippocampal tissue were significantly elevated in male EKyn offspring during the middle of the light phase (ZT 6), supporting our findings from previous studies evaluating brain tissue KYNA content in EKyn compared to ECon offspring (25)(26)(27)33). We presently selected the time points that correspond to transitions between the light and dark phases for rodents, as we previously studied time points that corresponded to the middle of the light and dark phases for rodents (27). As such, we determined that female offspring had conspicuously higher tryptophan, kynurenine, and KYNA levels in the plasma compared to males.…”

“…Further, the prenatal period has been found critical for elevations in KYNA to cause long term biochemical changes and cognitive dysfunction in adult rats (23)(24)(25)(26). Hence, to further investigate the neurodevelopmental impacts of KYNA elevation, we utilize the embryonic kynurenine (EKyn) paradigm in rats, wherein pregnant Wistar dams are fed 100 mg of kynurenine-laced chow daily from embryonic day (ED) 15 to ED 22 (25,27) (Figure 1B). This time course corresponds to the second trimester in human pregnancy, when the developing fetus is most vulnerable to exposure from infection or injury, thereby providing a translational model for in utero insults that instigate neurodevelopmental abnormalities (28)(29)(30).…”

“…We recently determined conspicuous sex and time of day dependent changes in sleep, home cage activity, and arousal in Abbreviations: SZ, schizophrenia; BD, bipolar disorder; KYNA, kynurenic acid; EKyn, embryonic kynurenine treatment; ECon, embryonic control treatment; ZT, zeitgeber time; KP, kynurenine pathway; KYNA, kynurenic acid; NMDA, pertaining to the N-methyl-D-aspartate glutamate receptor; GABA, γ-aminobutyric acid; α7nACh, pertaining to the alpha 7 nicotinic acetylcholine receptor; ED, embryonic day; PD, postnatal day; AP, anteriorposterior; LM, lateral-medial; DV, dorsal-ventral; HPLC, high-performance liquid chromatography; UHPLC, ultra high-performance liquid chromatography; KAT II, kynurenine amino transferase II; REM, rapid eye movement. young adult EKyn offspring (27). In a behavioral context, sleep and arousal states depend on hippocampal neuromodulation to regulate memory consolidation, retrieval, and locomotor activity (36,37).…”