Activation of alpha-2 adrenoceptors in locus coeruleus alleviates prenatal lipopolysaccharide-induced cognitive deficits in the offspring of rats

Abstract

The locus coeruleus (LC), the brain’s principal source of norepinephrine, critically regulates cognitive function. While our previous work established that prenatal lipopolysaccharide (LPS) exposure causes cognitive deficits in rat offspring, the underlying mechanisms and potential therapeutic targets remained unknown. In this study, we found that prenatal LPS exposure enhanced LC neuronal electrical activity and upregulated α2-adrenoceptors, tyrosine hydroxylase in the LC of 15-month-old rat offspring. Concurrently, both the LC and hippocampus exhibited Alzheimer’s disease (AD)-like pathologies, including hyperphosphorylated tau, elevated Aβ42, and increased BACE1 and GSK3β expression in rat offspring. Notably, prenatal dexmedetomidine treatment, a highly selective α2-adrenoceptor agonist, significantly improved cognition and reversed these molecular and electrophysiological alterations. Direct microinjection of dexmedetomidine into the LC similarly suppressed hyperactive LC neurons. In conclusion, α-2 adrenoceptor receptors in LC plays an important role in cognitive deficits induced by prenatal LPS exposure, and Dexmedetomidine might be a promising agent in treating prenatal LPS-induced cognitive deficits in offspring rats.