Kynurenic Acid and Sleep: Focus on Maternal and Offspring Health

Tryptophan metabolism via the kynurenine pathway (KP) and kynurenic acid (KYNA) accumulation occurs with prenatal insults, including maternal immune activation or excessive stress. Our goal is to investigate mechanistically how specifically elevating KYNA during pregnancy influences maternal sleep and the prenatal environment to produce negative outcomes

in the offspring. KYNA is of particular interest because it is an endogenous antagonist of α7nACh and NMDA receptors. Increased KYNA levels reduce neurotransmission, disrupt sleep architecture, and impair cognition. Increased brain KYNA levels (post-mortem or cerebrospinal fluid analysis) are found also in individuals with neurodevelopmental dysfunction. We will explore

the novel hypothesis that accumulated KYNA and elevated KP metabolism, a common denominator driving homeostatic disruption, exacerbates sleep problems during pregnancy and contributes to disrupted neurochemical stability, sleep, and cognitive function in young adult offspring. We predict that reducing KYNA by (i) targeting its primary synthesizing enzyme

kynurenine aminotransferase II (KAT II) or (ii) mechanistically interfering with its sites of action will lead to improved maternal sleep dynamics and offspring outcomes. KP metabolism and KYNA levels will be increased by feeding kynurenine-laced chow to pregnant rats (‘EKyn diet’). We will test the predictions that excessive prenatal KYNA plays a mechanistic role in a) poor sleep during

pregnancy and b) contributes to long-lasting neurochemical and behavioral abnormalities in offspring. Aim 1: Define sleep problems during pregnancy when KYNA formation is up-regulated. Hypothesis: Elevated KYNA in dams deteriorates sleep during pregnancy and targeted inhibition of KAT II can improve sleep quality. Aim 2: Treat neurochemical abnormalities underlying long-

lasting poor outcomes (sleep and cognition) in adult offspring from elevated kynurenine during prenatal period (EKyn diet). Hypothesis: Elevated brain KYNA in EKyn offspring drives neurochemical imbalances, deficits in sleep and learning behavior. Aim 3: Prevent adverse behavioral endophenotypes in offspring via choline-supplementation or dual-orexin receptor

antagonism during prenatal kynurenine treatment (EKyn diet). Adverse consequences of elevated KYNA during pregnancy can be mitigated by potentiation the 𝛂7nACh-R via choline- supplementation during neurodevelopment. Dual-orexin receptor antagonism in pregnant rats will attenuate maternal sleep disruptions. The proposed research will advance our understanding of

common molecular mechanisms between a neurodevelopmental insult, sleep disturbances and neurocognitive impairments, paving the way for novel therapies to alleviate these outcomes.