title: Prenatal alcohol exposure modifies glucocorticoid receptor subcellular distribution in the medial prefrontal cortex and impairs frontal cortex-dependent learning.
abstract: Prenatal alcohol exposure (PAE) has been shown to impair learning, memory and executive functioning in children. Perseveration, or the failure to respond adaptively to changing contingencies, is a hallmark on neurobehavioral assessment tasks for human fetal alcohol spectrum disorder (FASD). Adaptive responding is predominantly a product of the medial prefrontal cortex (mPFC) and is regulated by corticosteroids. In our mouse model of PAE we recently reported deficits in hippocampal formation-dependent learning and memory and a dysregulation of hippocampal formation glucocorticoid receptor (GR) subcellular distribution. Here, we examined the effect of PAE on frontal cortical-dependent behavior, as well as mPFC GR subcellular distribution and the levels of regulators of intracellular GR transport. PAE mice displayed significantly reduced response flexibility in a Y-maze reversal learning task. While the levels of total nuclear GR were reduced in PAE mPFC, levels of GR phosphorylated at serines 203, 211 and 226 were not significantly changed. Cytosolic, but not nuclear, MR levels were elevated in the PAE mPFC. The levels of critical GR trafficking proteins, FKBP51, Hsp90, cyclophilin 40, dynamitin and dynein intermediate chain, were altered in PAE mice, in favor of the exclusion of GR from the nucleus, indicating dysregulation of GR trafficking. Our findings suggest that there may be a link between a deficit in GR nuclear localization and frontal cortical learning deficits in prenatal alcohol-exposed mice.
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Allan
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Goggin
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Caldwell
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000378:metabolism* / Q000523:psychology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000523:psychology; D021381:Protein Transport; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012193:Reversal Learning / Q000187:drug effects; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D000431:Ethanol; D018841:HSP90 Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C000631446:PPIF protein, mouse; C403485:tacrolimus binding protein 4
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