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

Courtney J Wright,Katherine M Rentschler,Sarah Beggiato,Ashley M Lewis,Ana Pocivavsek,Nathan T J Wagner

doi:10.3389/fpsyt.2021.734984

Courtney J Wright, Katherine M Rentschler + Show 4 more

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https://doi.org/10.3389/fpsyt.2021.734984

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Abstract

Hypofunction of glutamatergic signaling is causally linked to neurodevelopmental disorders, including psychotic disorders like schizophrenia and bipolar disorder. Kynurenic acid (KYNA) has been found to be elevated in postmortem brain tissue and cerebrospinal fluid of patients with psychotic illnesses and may be involved in the hypoglutamatergia and cognitive dysfunction experienced by these patients. As insults during the prenatal period are hypothesized to be linked to the pathophysiology of psychotic disorders, we presently utilized the embryonic kynurenine (EKyn) paradigm to induce a prenatal hit. Pregnant Wistar dams were fed chow laced with kynurenine to stimulate fetal brain KYNA elevation from embryonic day 15 to embryonic day 22. Control dams (ECon) were fed unlaced chow. Plasma and hippocampal tissue from young adult (postnatal day 56) ECon and EKyn male and female offspring were collected at the beginning of the light (Zeitgeber time, ZT 0) and dark (ZT 12) phases to assess kynurenine pathway metabolites. Hippocampal tissue was also collected at ZT 6 and ZT 18. In separate animals, in vivo microdialysis was conducted in the dorsal hippocampus to assess extracellular KYNA, glutamate, and γ-aminobutyric acid (GABA). Biochemical analyses revealed no changes in peripheral metabolites, yet hippocampal tissue KYNA levels were significantly impacted by EKyn treatment, and increased in male EKyn offspring at ZT 6. Interestingly, extracellular hippocampal KYNA levels were only elevated in male EKyn offspring during the light phase. Decreases in extracellular glutamate levels were found in the dorsal hippocampus of EKyn male and female offspring, while decreased GABA levels were present only in males during the dark phase. The current findings suggest that the EKyn paradigm may be a useful tool for investigation of sex- and time-dependent changes in hippocampal neuromodulation elicited by prenatal KYNA elevation, which may influence behavioral phenotypes and have translational relevance to psychotic disorders.

Highlights

Disruptions in neurotransmission are associated with the pathology of psychotic disorders such as schizophrenia (SZ) and bipolar disorder (BD)
Hippocampal kynurenic acid (KYNA) was significantly impacted by embryonic kynurenine (EKyn) treatment (F1,107 = 4.879, P = 0.0293), with increased KYNA in hippocampal tissue in EKyn across the light phase, and post-hoc in EKyn males at ZT6 compared to embryonic day 22. Control dams (ECon) (P = 0.0500; Figure 3)
We presently confirmed that prenatal KYNA elevation results in elevated tissue KYNA levels and extracellular KYNA levels in the hippocampus of young adult male EKyn offspring [21, 25, 26]

Summary

Introduction

Disruptions in neurotransmission are associated with the pathology of psychotic disorders such as schizophrenia (SZ) and bipolar disorder (BD). Dysregulated modulation of the excitatory neurotransmitter glutamate and the inhibitory small molecule y-aminobutyric acid (GABA) has been implicated in the etiology of cognitive, negative, and positive symptoms in individuals with severe psychiatric illness [1,2,3,4]. Hypofunction of the cortical ionotropic glutamate receptor N-methyl-daspartate (NMDA) is thought to contribute to dysregulated tonic GABAergic inhibition, alterations in cortical glutamate levels, and the pathophysiological manifestation of cognitive and negative symptoms in individuals with SZ [2]. KYNA is of particular interest as it competitively antagonizes NMDA receptors at the glycine site, and inhibits α7 nicotinic acetylcholine (α7nACh) receptors, thereby directly influencing neurotransmission [11,12,13,14]. Preclinical studies in animal models postulate that increased KYNA impairs learning and memory, especially in brain regions like the prefrontal cortex and hippocampus, whereas KYNA reductions may feasibly improve learning and memory [16,17,18,19,20,21,22]

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