Ablation of Gabra5 Influences Corticosterone Levels and Anxiety-like Behavior in Mice

Stress responses are activated by the hypothalamic-pituitary-adrenal axis (HPA axis), culminating in the release of glucocorticoids. During prolonged periods of secretion of glucocorticoids or inappropriate behavioral responses to a stressor, pathologic conditions may occur. Increased glucocorticoid concentration is linked to generalized anxiety, and there are knowledge gaps regarding its regulation. It is known that the HPA axis is under GABAergic control, but the contribution of the individual subunits of the GABA receptor is largely unknown. In this study, we investigated the relationship between the α5 subunit and corticosterone levels in a new mouse model deficient for Gabra5, which is known to be linked to anxiety disorders in humans and phenologs observed in mice. We observed decreased rearing behavior, suggesting lower anxiety in the Gabra5−/− animals; however, such a phenotype was absent in the open field and elevated plus maze tests. In addition to decreased rearing behavior, we also found decreased levels of fecal corticosterone metabolites in Gabra5−/− mice indicating a lowered stress response. Moreover, based on the electrophysiological recordings where we observed a hyperpolarized state of hippocampal neurons, we hypothesize that the constitutive ablation of the Gabra5 gene leads to functional compensation with other channels or GABA receptor subunits in this model.

[1]  Woong Sun,et al.  The Neomycin Resistance Cassette in the Targeted Allele of Shank3B Knock-Out Mice Has Potential Off-Target Effects to Produce an Unusual Shank3 Isoform , 2021, Frontiers in Molecular Neuroscience.

[2]  I. J. Lynch,et al.  A non-invasive method to study evolution of extracellular fluid volume in mice using time domain nuclear magnetic resonance. , 2020, American journal of physiology. Renal physiology.

[3]  R. Sedláček,et al.  CRISPR/Cas9 Epigenome Editing Potential for Rare Imprinting Diseases: A Review , 2020, Cells.

[4]  J. Seckl,et al.  Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats , 2020, Molecular metabolism.

[5]  W. Browne,et al.  Cage aggression in group-housed laboratory male mice: an international data crowdsourcing project , 2019, Scientific Reports.

[6]  Tija C Jacob,et al.  Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors , 2019, Front. Mol. Neurosci..

[7]  R. Francavilla,et al.  Input-Specific Synaptic Location and Function of the α5 GABAA Receptor Subunit in the Mouse CA1 Hippocampal Neurons , 2018, The Journal of Neuroscience.

[8]  P. Germain,et al.  Exploratory rearing: a context- and stress-sensitive behavior recorded in the open-field test , 2018, Stress.

[9]  J. Swinny,et al.  Molecular Characterization of GABA-A Receptor Subunit Diversity within Major Peripheral Organs and Their Plasticity in Response to Early Life Psychosocial Stress , 2018, Front. Mol. Neurosci..

[10]  L. Paninski,et al.  Anxiety Cells in a Hippocampal-Hypothalamic Circuit , 2018, Neuron.

[11]  D. Hume,et al.  Glucocorticoid Receptor Binding Induces Rapid and Prolonged Large-Scale Chromatin Decompaction at Multiple Target Loci , 2017, Cell reports.

[12]  Didier Y. R. Stainier,et al.  Genetic compensation: A phenomenon in search of mechanisms , 2017, PLoS genetics.

[13]  L. Schmidt,et al.  The role of glucocorticoids and corticotropin-releasing hormone regulation on anxiety symptoms and response to treatment , 2017, Endocrine connections.

[14]  B. Orser,et al.  Sex-Dependent Anti-Stress Effect of an α5 Subunit Containing GABAA Receptor Positive Allosteric Modulator , 2016, Front. Pharmacol..

[15]  B. Yee,et al.  A Pharmacogenetic ‘Restriction-of-Function’ Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by α5-Containing GABAA Receptors in Mice , 2016, Neuropsychopharmacology.

[16]  J. Herman,et al.  Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. , 2016, Comprehensive Physiology.

[17]  K. Pang,et al.  The Role of the Hippocampus in Avoidance Learning and Anxiety Vulnerability , 2014, Front. Behav. Neurosci..

[18]  Vootele Voikar,et al.  Assessment of mouse anxiety-like behavior in the light–dark box and open-field arena: Role of equipment and procedure , 2014, Physiology & Behavior.

[19]  M. Weissman,et al.  Evidence for Linkage and Association of GABRB3 and GABRA5 to Panic Disorder , 2014, Neuropsychopharmacology.

[20]  L. Bird.  Angelman syndrome: review of clinical and molecular aspects , 2014, The application of clinical genetics.

[21]  J. Herman,et al.  Glucocorticoid actions on synapses, circuits, and behavior: Implications for the energetics of stress , 2014, Frontiers in Neuroendocrinology.

[22]  Keizo Takao,et al.  Contextual and Cued Fear Conditioning Test Using a Video Analyzing System in Mice , 2014, Journal of visualized experiments : JoVE.

[23]  Patricia M. Goodnite Rn-Bc.  Stress: A Concept Analysis , 2013 .

[24]  B. Orser,et al.  Hyperpolarization-Activated Current (Ih) Is Reduced in Hippocampal Neurons from Gabra5−/− Mice , 2013, PloS one.

[25]  Jennifer W. Hill.  PVN pathways controlling energy homeostasis , 2012, Indian journal of endocrinology and metabolism.

[26]  R. Pocock,et al.  Neuronal Responses to Physiological Stress , 2012, Front. Gene..

[27]  S. Moss,et al.  Neurosteroidogenesis Is Required for the Physiological Response to Stress: Role of Neurosteroid-Sensitive GABAA Receptors , 2011, The Journal of Neuroscience.

[28]  J. Cryan,et al.  The age of anxiety: role of animal models of anxiolytic action in drug discovery , 2011, British journal of pharmacology.

[29]  J. Lambert,et al.  Neurosteroids and GABAA Receptor Interactions: A Focus on Stress , 2011, Front. Neurosci..

[30]  I. Liberzon,et al.  The Neurocircuitry of Fear, Stress, and Anxiety Disorders , 2011, Neuropsychopharmacology.

[31]  Loren J. Martin,et al.  α5GABAA Receptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory , 2010, Journal of Neuroscience.

[32]  Loren J. Martin,et al.  The physiological properties and therapeutic potential of alpha5-GABAA receptors. , 2009, Biochemical Society transactions.

[33]  Loren J. Martin,et al.  Etomidate Targets α5 γ-Aminobutyric Acid Subtype A Receptors to Regulate Synaptic Plasticity and Memory Blockade , 2009, Anesthesiology.

[34]  R. Olsen,et al.  GABAA receptors: Subtypes provide diversity of function and pharmacology , 2009, Neuropharmacology.

[35]  J. Herman,et al.  Functional role of local GABAergic influences on the HPA axis , 2008, Brain Structure and Function.

[36]  R. Sapolsky,et al.  Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy , 2008, Proceedings of the National Academy of Sciences.

[37]  Edward O. Mann,et al.  Which GABAA Receptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus? , 2008, The Journal of Neuroscience.

[38]  Loren J. Martin,et al.  α5GABAA Receptors Regulate the Intrinsic Excitability of Mouse Hippocampal Pyramidal Neurons , 2007 .

[39]  W. Vale,et al.  The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress , 2006, Dialogues in clinical neuroscience.

[40]  A. D. De Blas,et al.  Synaptic and nonsynaptic localization of GABAA receptors containing the α5 subunit in the rat brain , 2006 .

[41]  I. Módy,et al.  Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA A receptor alpha5 subunit-deficient mice. , 2006, Journal of neurophysiology.

[42]  G. Tabacchi,et al.  Testosterone and aggressiveness. , 2005, Medical science monitor : international medical journal of experimental and clinical research.

[43]  B. Orser,et al.  Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors , 2004 .

[44]  E. Burón,et al.  Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the alpha-5 subunit, in the elevated plus-maze test , 2002, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[45]  F. Kuenzi,et al.  Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABAAReceptor , 2002, The Journal of Neuroscience.

[46]  K. Vogt,et al.  Trace fear conditioning involves hippocampal α5 GABAA receptors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[47]  William Wisden,et al.  Adaptive regulation of neuronal excitability by a voltage- independent potassium conductance , 2001, Nature.

[48]  S. Watson,et al.  Fos expression in forebrain afferents to the hypothalamic paraventricular nucleus following swim stress , 1996, The Journal of comparative neurology.

[49]  J. Slangen,et al.  Animal Models in Psychopharmacology , 1991, APS: Advances in Pharmacological Sciences.

[50]  V. Starcevic,et al.  Role of Benzodiazepines in Anxiety Disorders. , 2020, Advances in experimental medicine and biology.

[51]  P. Gasser.  41 – Rapid Corticosteroid Actions on Behavior: Mechanisms and Implications , 2009 .

[52]  J. O’Keefe,et al.  Rearing on Hind Legs, Environmental Novelty, and the Hippocampal Formation , 2006, Reviews in the neurosciences.

[53]  Robert M. Sapolsky,et al.  Why Zebras Don't Get Ulcers , 1994 .

[54]  Duncan C. Blanchard,et al.  Risk assessment in animal models of anxiety , 1991 .