title: 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.
authors.affiliation: Department of Psychology, Northeastern University, Boston, MA, USA.
authors.forename: Prabarna
authors.initials: P
authors.lastname: Ganguly
authors.affiliation: Department of Psychology, Northeastern University, Boston, MA, USA.
authors.forename: Freedom H
authors.initials: FH
authors.lastname: Holland
authors.affiliation: Department of Psychology, Northeastern University, Boston, MA, USA.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Brenhouse
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000076122:Disks Large Homolog 4 Protein; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008426:Maternal Deprivation; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D001523:Mental Disorders / Q000209:etiology*; D010320:Parvalbumins / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013315:Stress, Psychological / Q000150:complications* / Q000209:etiology / Q000473:pathology*
chemical_list: D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010320:Parvalbumins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C501449:Dlg4 protein, rat