Functional Uncoupling NMDAR NR2A Subunit from PSD-95 in the Prefrontal Cortex: Effects on Behavioral Dysfunction and Parvalbumin Loss after Early-Life Stress

Abstract

Exposure to early-life stress increases vulnerability to psychiatric disorders, including depression, schizophrenia, and anxiety. Growing evidence implicates aberrant development of the prefrontal cortex (PFC) in the effects of early-life stress, which often emerge in adolescence or young adulthood. Specifically, early-life stress in the form of maternal separation (MS) in rodents has been shown to decrease parvalbumin (PVB)-positive interneurons in the adolescent PFC; however, the mechanism underpinning behavioral dysfunction and PVB loss is not yet known. We recently reported that MS causes overexpression of the NMDA subunit NR2A in the PFC of adolescent rats. Elevated PFC NR2A is also found in developmental models of schizophrenia and is correlated with behavioral deficits, acting largely through its association with the postsynaptic protein PSD-95. In addition, adolescent maturation of PVB-positive interneurons relies on NR2A-driven NMDA activity. Therefore, it is possible that the NR2A/PSD-95 signaling complex has a role in adolescent MS effects. Here, we aimed to determine whether a discrete manipulation of PFC NR2A could prevent MS effects on PFC-controlled behaviors, including cognition, anxiety, and novelty-induced hyperlocomotion, as well as PVB loss in adolescence. We intracranially infused the NR2A-specific blocking peptide TAT2A in order to uncouple NR2A from PSD-95 in the early-adolescent PFC, without antagonizing the NMDA receptor. We demonstrated that MS rats treated with TAT2A during early adolescence were protected from MS-induced PVB loss and exhibited less anxious behavior than those infused with control peptide. These data implicate NR2A-related N-methyl-D-aspartate receptor development in adolescent behavioral and neural consequences of early-life stress.

Cross-Generational Transmission of Early Life Stress Effects on HPA Regulators and Bdnf Are Mediated by Sex, Lineage, and Upbringing

“…With regards to behavior, ELS-exposed subjects were more active than control subjects upon introduction to the open field arena, which may reflect a higher response to novelty that we have previously reported (Ganguly et al, 2015). Surprisingly, while ELS has been repeatedly shown to increase anxiety-like behaviors (Koe et al, 2016), here we observed that even after correcting for increased general locomotion, females exposed to ELS visited the center of the open field more often than control subjects—typically a measure of lower anxiety.…”

Npas4 deficiency and prenatal stress interact to affect social recognition in mice

“…Furthermore, Npas4 deficiency has not been associated with increased anxiety‐like behavior in past studies using male mice, while PNS has been shown to induce anxiety‐like behavior in both sexes in adulthood . The PFC is a known contributor to the regulation of anxiety and environmentally induced loss of prefrontal PV during development has been associated with increased anxiety‐like behaviors (ie, References ). Thus the reduced number of PV‐expressing cells in the PFC of HET mice, when associated with other PNS‐induced dysregulation (eg, increased corticotrophin‐releasing hormone (CRH) in the amygdala) could contribute to the reduced time spent in the center of the open‐field observed in PNS HET mice.…”

Synaptic Plasticity, Metaplasticity and Depression

“…During gestation, excessive maternal stress or glucocorticoid treatment causes adult offspring to exhibit increased anxiety-like and depression-like behaviors, as well as impaired learning [ 101 ]. Adolescent rats that received maternal separation stress as young pups have excess anxiety and overexpress NR2A, a NMDAR subunit [ 102 ]. Adult mice that were deprived of bedding early in life show increased aggression and impaired social recognition [ 103 ].…”