title: Embryonic GABA(B) receptor blockade alters cell migration, adult hypothalamic structure, and anxiety- and depression-like behaviors sex specifically in mice.
abstract: Neurons of the paraventricular nucleus of the hypothalamus (PVN) regulate the hypothalamic- pituitary-adrenal (HPA) axis and the autonomic nervous system. Females lacking functional GABA(B) receptors because of a genetic disruption of the R1 subunit have altered cellular characteristics in and around the PVN at birth. The genetic disruption precluded appropriate assessments of physiology or behavior in adulthood. The current study was conducted to test the long term impact of a temporally restricting pharmacological blockade of the GABA(B) receptor to a 7-day critical period (E11-E17) during embryonic development. Experiments tested the role of GABA(B) receptor signaling in fetal development of the PVN and later adult capacities for adult stress related behaviors and physiology. In organotypic slices containing fetal PVN, there was a female specific, 52% increase in cell movement speeds with GABA(B) receptor antagonist treatment that was consistent with a sex-dependent lateral displacement of cells in vivo following 7 days of fetal exposure to GABA(B) receptor antagonist. Anxiety-like and depression-like behaviors, open-field activity, and HPA mediated responses to restraint stress were measured in adult offspring of mothers treated with GABA(B) receptor antagonist. Embryonic exposure to GABA(B) receptor antagonist resulted in reduced HPA axis activation following restraint stress and reduced depression-like behaviors. There was also increased anxiety-like behavior selectively in females and hyperactivity in males. A sex dependent response to disruptions of GABA(B) receptor signaling was identified for PVN formation and key aspects of physiology and behavior. These changes correspond to sex specific prevalence in similar human disorders, namely anxiety disorders and hyperactivity.
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Stratton
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Staros
authors.affiliation: Center for Animal Genomics, Veterinary Faculty, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Tomaz
authors.initials: T
authors.lastname: Budefeld
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Searcy
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Connor
authors.initials: C
authors.lastname: Nash
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Chad
authors.initials: C
authors.lastname: Eitel
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Carbone
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Handa
authors.affiliation: Center for Animal Genomics, Veterinary Faculty, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Gregor
authors.initials: G
authors.lastname: Majdic
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America; School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Tobet
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D003863:Depression / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004622:Embryo, Mammalian; D005260:Female; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology*; D015870:Gene Expression; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D007103:Immobilization; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D010721:Phosphinic Acids / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011412:Propanolamines / Q000494:pharmacology; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics*; D011595:Psychomotor Agitation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018080:Receptors, GABA-B / Q000172:deficiency / Q000235:genetics*; D012737:Sex Factors; D013315:Stress, Psychological / Q000503:physiopathology; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D058788:GABA-B Receptor Antagonists; D010721:Phosphinic Acids; D011412:Propanolamines; D021122:Protein Subunits; D018080:Receptors, GABA-B; C085075:CGP 55845A; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; C057491:2-hydroxysaclofen