Developmental Perturbation of the Kynurenine Pathway Shapes Adult Sensorimotor Processing and Behavioral Responses to...

The kynurenine pathway (KP) plays a critical role in brain development by generating neuroactive metabolites that regulate glutamatergic and cholinergic neurotransmission. Although developmental disturbances of KP metabolism have been associated with long-term neurobehavioral abnormalities, it remains unclear whether early-life KP perturbation produces persistent alterations in adult sensorimotor function and behavioral responses to pharmacological challenges. In this study, we combined constitutive kynurenine 3-monooxygenase (KMO) deficiency with prenatal kynurenine (KYN) exposure to investigate their long-term effects on brain kynurenic acid (KYNA) concentrations, acoustic startle reactivity and prepulse inhibition (PPI) following acute administration of the cannabinoid receptor agonist JWH-018 in adult male wild-type (WT) and Kmo^-/- mice. Constitutive KMO deficiency markedly increased adult brain KYNA concentrations, whereas prenatal KYN exposure (10 mg/dam/day) did not produce sustained elevations in whole-brain KYNA. Nevertheless, prenatal KYN exposure was associated with long-lasting alterations in sensorimotor function. Kmo^-/- mice exhibited enhanced baseline acoustic startle reactivity and higher baseline PPI compared with WT mice. Prenatal KYN exposure attenuated the elevated baseline startle response observed in Kmo^-/- mice, whereas its influence on baseline PPI was more limited. Following acute JWH-018 administration, changes in acoustic startle reactivity differed according to prenatal treatment, whereas changes in PPI were primarily associated with genotype, with WT mice generally exhibiting larger positive changes than Kmo^-/- mice. The intensity-dependent profile of PPI changes was also influenced by prenatal treatment. Together, these findings indicate that transient prenatal KP perturbation can be associated with persistent alterations in adult sensorimotor function even in the absence of sustained elevations in whole-brain KYNA. They further suggest that developmental KP history and constitutive KMO deficiency are associated with distinct patterns of behavioral changes observed following cannabinoid receptor activation, highlighting the complex relationship between developmental metabolic perturbations and adult sensorimotor processing.