Embryonic GABAB Receptor Blockade Alters Cell Migration, Adult Hypothalamic Structure, and Anxiety- and Depression-Like Behaviors Sex Specifically in Mice

• Published in: PloS one Vol. 9; no. 8; p. e106015
• Main Authors: Stratton, Matthew S., Staros, Michelle, Budefeld, Tomaz, Searcy, Brian T., Nash, Connor, Eitel, Chad, Carbone, David, Handa, Robert J., Majdic, Gregor, Tobet, Stuart A.
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 27-08-2014
• Subjects: Anxiety; Autonomic nervous system; Biology and Life Sciences; Brain; Cardiovascular disease; Cell division; Cell migration; Critical period; Disorders; Embryogenesis; Embryonic growth stage; Exposure; Females; Fetuses; Gender differences; Gene expression; Genomics; Human behavior; Hyperactivity; Hypothalamic-pituitary-adrenal axis; Hypothalamus; In vivo methods and tests; Lateral displacement; Males; Mental depression; Offspring; Open-field behavior; Paraventricular nucleus; Pharmacology; Physiology; Pituitary; Prenatal exposure; Psychiatry; Receptors; Research and Analysis Methods; Rodents; Sex; Sexual behavior; Signaling; Stress; Stresses; γ-Aminobutyric acid B receptors; Slovenia; United States > US; Colorado; Arizona
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0106015

Neurons of the paraventricular nucleus of the hypothalamus (PVN) regulate the hypothalamic- pituitary-adrenal (HPA) axis and the autonomic nervous system. Females lacking functional GABAB 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 GABAB receptor to a 7-day critical period (E11–E17) during embryonic development. Experiments tested the role of GABAB 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 GABAB receptor antagonist treatment that was consistent with a sex-dependent lateral displacement of cells in vivo following 7 days of fetal exposure to GABAB 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 GABAB receptor antagonist. Embryonic exposure to GABAB 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 GABAB 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.