0197 Increased Brain Kynurenic Acid Elicits Sex-Dependent Abnormalities in NREM Sleep Spindle Dynamics

Abstract

Abstract Introduction Sleep spindles are thalamocortical oscillations which occur during non-rapid eye movement (NREM) sleep. NREM sleep spindle aberrations are a consistent clinical sleep deficiency associated with psychotic disorders and exacerbation of cognitive symptoms. Kynurenic acid (KYNA), a tryptophan metabolite synthesized from kynurenine via kynurenine aminotransferases (KATs) and modulator of glutamatergic and cholinergic neurotransmission, is elevated in the brain of patients with psychotic disorders, including schizophrenia and bipolar disorder. Currently, we sought to understand the neurodevelopmental and transient impacts of brain KYNA elevation on sleep spindle dynamics. Methods In Experiment #1, sleep spindles were evaluated in adult offspring, postnatal day (PD) 56 from embryonic kynurenine (EKyn) treated rat dams (Rentschler et al., 2021 Sz Bull) (N=7-9 per group). EKyn KYNA male, but not female, offspring have elevated KYNA during the light phase (Wright et al., 2021 Frontiers in Psychiatry). In Experiment #2, sleep spindles were evaluated in adult rats injected with kynurenine (100 mg/kg; i.p.) to acutely elevate brain KYNA levels at zeitgeber time 0 (N=8-12 per group). Polysomnography was recorded via EEG/EMG telemetry. Sleep spindles were evaluated using a custom-made manual scoring system during the first 4 hr of the light cycle. Results Male EKyn, but not female, exhibited a decrease in spindle density compared to ECon (2-wayANOVA: ***P<0.001). FFT spectral power for peak spindle frequency (10-15 Hz) was reduced for all EKyn offspring (3-way ANOVA; frequency x treatment interaction: ****P<0.0001; treatment: *P<0.05). Kynurenine challenge reduced spindle density for both sexes (2-way ANOVA: ***P<0.001; M: **P<0.01; F: *P<0.05). Frequency x treatment interaction for males (2-way ANOVA: ***P<0.001) was observed with lower FFT spectral power for 10-10.5 Hz (*P<0.05) and greater power for 14-14.5 Hz (*P<0.05). Conclusion We determined conspicuous sex differences in spindle dynamics in the EKyn paradigm that may be related to brain KYNA levels; only males exhibited a decrease in spindle density, however all EKyn offspring had reduced FFT spectral power. Kynurenine challenge reduced spindle density in both sexes, however only males had changes in FFT spectral power. Future work will consider the efficacy of KYNA synthesis inhibition to prevent NREM sleep spindle abnormalities induced by KYNA elevation. Support (If Any) Funding Source: National Institute of Health Grants: NIH RO1 NS102209 & P50 MH103222.