PI3K/AKT signaling contributes to prenatal nicotine exposure-induced developmental impairment of the pontomedullary respiratory network in neonatal rats.

Prenatal nicotine exposure (PNE) disrupts the development of the pontomedullary respiratory network and increases susceptibility to respiratory dysfunction after birth. However, the role of PI3K/AKT signaling in PNE-induced impairment of neuronal development within the pontomedullary respiratory network remains unclear. In this study, a rat model of PNE was established to investigate neuronal development, apoptosis, microglial activation, and PI3K/AKT signaling within respiratory-related nuclei of the pontomedullary network in neonatal rats on postnatal day 2. PNE induced neuronal morphological abnormalities and reduced NeuN-positive neuronal populations in the VIIn/pFRG, XIIn, and NA/pre-BötC regions. These changes were accompanied by increased TUNEL-positive cells, elevated caspase-3 and caspase-9 expression, enhanced microglial activation as indicated by increased Iba-1-positive cells, and increased PIK3CA expression and the p-AKT1/AKT1 ratio. Pharmacological inhibition of PI3K/AKT signaling with wortmannin partially attenuated neuronal development impairment, apoptosis, and microglial activation. PNE was also associated with reduced neonatal body weight and length. These findings provide pharmacological evidence that dysregulated PI3K/AKT signaling contributes to PNE-induced developmental impairment of the pontomedullary respiratory network, potentially through processes involving neuronal apoptosis and microglial activation.