Maternal sleep disordered breathing during gestation produces sexually dimorphic autism‐relevant synaptic and behavioral aberrations in the offspring associated with excessive mTOR cortical signaling

Abstract

Sleep disordered breathing (SDB) is characterized by recurring breathing cessations during sleep, causing intermittent hypoxia (oxygen deprivation) often several hundred times per night. Obstructive sleep apnea is the most common form of SDB in pregnancy, and confers risk for detrimental maternal‐fetal outcomes. Although many of the maternal risk factors for the onset SDB during pregnancy and the development of autism spectrum disorders (ASD) in her offspring are highly overlapping (e.g., maternal obesity, advanced maternal age), no studies to date have empirically investigated the potential link between these conditions. We subjected pregnant rat dams to intermittent hypoxia or normoxia (GIH and GNX, respectively) from gestation day 10‐21 to investigate the consequences of maternal SDB on offspring neural function. We found that male GIH offspring exhibited deficits in several behaviors which were accompanied by increased pyramidal neuron dendritic spine density in the medial prefrontal cortex (PFC). These effects appear to arise from a disruption of normal developmental synaptic pruning late in childhood and persisting into early adolescence. The mTOR kinase signal transduction pathway has emerged as a critical regulator of dendritic spine formation, and dysregulation of key components of this pathway are implicated in the etiology of the increased cortical dendritic spine density of ASD. Additionally, we found that mTOR is aberrantly activated in the prefrontal cortex of male GIH offspring. Furthermore, inhibition of mTOR by rapamycin treatment significantly reduced behavioral abnormalities within GIH offspring. These findings suggest an opportunity for clinical intervention for offspring of the SDB maternal model by targeting the mTOR signaling pathway.