Glucocorticoid receptor dysregulation underlies 5-HT_2AR-dependent synaptic and behavioral deficits in a mouse neurodevelopmental disorder model

Prenatal environmental insults increase the risk of neurodevelopmental psychiatric conditions in the offspring. Structural modifications of dendritic spines are central to brain development and plasticity. Using maternal immune activation (MIA) as a rodent model of prenatal environmental insult, previous results have reported dendritic structural deficits in the frontal cortex. However, very little is known about the molecular mechanism underlying MIA-induced synaptic structural alterations in the offspring. Using prenatal (E12.5) injection with polyinosinic–polycytidylic acid potassium salt as a mouse MIA model, we show here that upregulation of the serotonin 5-HT_2A receptor (5-HT_2AR) is at least in part responsible for some of the effects of prenatal insults on frontal cortex dendritic spine structure and sensorimotor gating processes. Mechanistically, we report that this upregulation of frontal cortex 5-HT_2AR expression is associated with MIA-induced reduction of nuclear translocation of the glucocorticoid receptor (GR) and, consequently, a decrease in the enrichment of GR at the 5-HT_2AR promoter. The translational significance of these preclinical findings is supported by data in postmortem human brain samples suggesting dysregulation of GR translocation in frontal cortex of schizophrenia subjects. We also found that repeated corticosterone administration augmented frontal cortex 5-HT_2AR expression and reduced GR binding to the 5-HT_2AR promoter. However, virally (adeno-associated virus) mediated augmentation of GR function reduced frontal cortex 5-HT_2AR expression and improved sensorimotor gating processes via 5-HT_2AR. Together, these data support a negative regulatory relationship between GR signaling and 5-HT_2AR expression in the mouse frontal cortex that may carry implications for the pathophysiology underlying 5-HT_2AR dysregulation in neurodevelopmental psychiatric disorders.