GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology

GABAergic mechanisms are critically involved in the control of fear and anxiety, but their role in the development of stress-induced psychopathologies, including post-traumatic stress disorder (PTSD) and mood disorders is not sufficiently understood. We studied these functions in two established mouse models of risk factors for stress-induced psychopathologies employing variable juvenile stress and/or social isolation. A battery of emotional tests in adulthood revealed the induction of contextually generalized fear, anxiety, hyperarousal and depression-like symptoms in these paradigms. These reflect the multitude and complexity of stress effects in human PTSD patients. With factor analysis we were able to identify parameters that reflect these different behavioral domains in stressed animals and thus provide a basis for an integrated scoring of affectedness more closely resembling the clinical situation than isolated parameters. To test the applicability of these models to genetic approaches we further tested the role of GABA using heterozygous mice with targeted mutation of the GABA synthesizing enzyme GAD65 [GAD65(+/−) mice], which show a delayed postnatal increase in tissue GABA content in limbic and cortical brain areas. Unexpectedly, GAD65(+/−) mice did not show changes in exploratory activity regardless of the stressor type and were after the variable juvenile stress procedure protected from the development of contextual generalization in an auditory fear conditioning experiment. Our data demonstrate the complex nature of behavioral alterations in rodent models of stress-related psychopathologies and suggest that GAD65 haplodeficiency, likely through its effect on the postnatal maturation of GABAergic transmission, conveys resilience to some of these stress-induced effects.

[1]  S. Totterdell,et al.  Sustained stress-induced changes in mice as a model for chronic depression , 2010, Psychopharmacology.

[2]  H. Anisman,et al.  Short- and long-periods of neonatal maternal separation differentially affect anxiety and feeding in adult rats: gender-dependent effects. , 1999, Brain research. Developmental brain research.

[3]  K. Ressler,et al.  Training‐induced changes in the expression of GABAA‐associated genes in the amygdala after the acquisition and extinction of Pavlovian fear , 2007, The European journal of neuroscience.

[4]  Rajeevan T. Narayanan,et al.  Deficiency of the 65 kDa Isoform of Glutamic Acid Decarboxylase Impairs Extinction of Cued But Not Contextual Fear Memory , 2009, The Journal of Neuroscience.

[5]  Joseph E LeDoux,et al.  Molecular Mechanisms of Fear Learning and Memory , 2011, Cell.

[6]  U. Heinemann,et al.  Long-Lasting Increase of Corticosterone After Fear Memory Reactivation: Anxiolytic Effects and Network Activity Modulation in the Ventral Hippocampus , 2013, Neuropsychopharmacology.

[7]  C. Wotjak,et al.  Toward an Animal Model of Posttraumatic Stress Disorder , 2006, Annals of the New York Academy of Sciences.

[8]  H. Anisman,et al.  Plasticity of the GABAA receptor subunit cassette in response to stressors in reactive versus resilient mice , 2010, Neuroscience.

[9]  Jamie D. Feusner,et al.  GABAA receptor β3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population , 2001, Psychiatry Research.

[10]  G. Moll,et al.  Generalization of contextual fear depends on associative rather than non-associative memory components , 2012, Behavioural Brain Research.

[11]  G. Richter-Levin,et al.  Juvenile stress induces a predisposition to either anxiety or depressive-like symptoms following stress in adulthood , 2007, European Neuropsychopharmacology.

[12]  S. Baekkeskov,et al.  Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Zohar,et al.  Post-traumatic stress disorder: facts and fiction , 2008, Current opinion in psychiatry.

[14]  K. Obata,et al.  Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65 , 2000, Brain Research.

[15]  J. Zohar,et al.  Pre-pubertal stress exposure affects adult behavioral response in association with changes in circulating corticosterone and brain-derived neurotrophic factor , 2009, Psychoneuroendocrinology.

[16]  Robert W. Williams,et al.  Strain Differences in Stress Responsivity Are Associated with Divergent Amygdala Gene Expression and Glutamate-Mediated Neuronal Excitability , 2010, The Journal of Neuroscience.

[17]  C. Nemeroff,et al.  The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies , 2001, Biological Psychiatry.

[18]  D. Nutt,et al.  Role of GABA in anxiety and depression , 2004, Eksperimental'naia i klinicheskaia farmakologiia.

[19]  J. Davidson,et al.  The Efficacy and Tolerability of Tiagabine in Adult Patients With Post-Traumatic Stress Disorder , 2007, Journal of clinical psychopharmacology.

[20]  K. Braun,et al.  Unpredictable chronic stress in juvenile or adult rats has opposite effects, respectively, promoting and impairing resilience , 2012, Stress.

[21]  G. Forster,et al.  Adult rats exposed to early-life social isolation exhibit increased anxiety and conditioned fear behavior, and altered hormonal stress responses , 2009, Hormones and Behavior.

[22]  O. Stork,et al.  Are NCAM deficient mice an animal model for schizophrenia? , 2012, Front. Behav. Neurosci..

[23]  J. Cryan,et al.  The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice , 2005, Neuroscience & Biobehavioral Reviews.

[24]  J. Zohar,et al.  Long-lasting behavioral effects of juvenile trauma in an animal model of PTSD associated with a failure of the autonomic nervous system to recover , 2007, European Neuropsychopharmacology.

[25]  Joseph E LeDoux,et al.  Response Variation following Trauma: A Translational Neuroscience Approach to Understanding PTSD , 2007, Neuron.

[26]  H. Anisman,et al.  Stressor exposure of male and female juvenile mice influences later responses to stressors: Modulation of GABAA receptor subunit mRNA expression , 2012, Neuroscience.

[27]  R. Novo,et al.  Exposure to stress differential vascular adaptive response in spontaneously hypertensive and Wistar rats: Role of nitric oxide, and prehypertensive and hypertensive states. , 2006, Life sciences.

[28]  A. Guidotti,et al.  Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder , 2008, Proceedings of the National Academy of Sciences.

[29]  H. Pape,et al.  Generalisation of conditioned fear and its behavioural expression in mice , 2003, Behavioural Brain Research.

[30]  G. Bernard,et al.  Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study , 2007, Critical care.

[31]  J. Krystal,et al.  GABA and glutamate systems as therapeutic targets in depression and mood disorders , 2005, Expert opinion on therapeutic targets.

[32]  J. Davidson,et al.  Divalproex in the Treatment of Posttraumatic Stress Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial in a Veteran Population , 2008, Journal of clinical psychopharmacology.

[33]  G. Vaiva,et al.  Relationship between posttrauma GABA plasma levels and PTSD at 1-year follow-up. , 2006, The American journal of psychiatry.

[34]  K. Obata,et al.  Role of glutamate decarboxylase (GAD) isoform, GAD65, in GABA synthesis and transport into synaptic vesicles—Evidence from GAD65-knockout mice studies , 2007, Brain Research.

[35]  Deanna L. Wallace,et al.  CREB regulation of nucleus accumbens excitability mediates social isolation–induced behavioral deficits , 2009, Nature Neuroscience.

[36]  G. Vaiva,et al.  Low posttrauma GABA plasma levels as a predictive factor in the development of acute posttraumatic stress disorder , 2004, Biological Psychiatry.

[37]  K. Obata,et al.  Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice , 2003, Genes, brain, and behavior.

[38]  D. Finn,et al.  Alterations in extracellular levels of gamma-aminobutyric acid in the rat basolateral amygdala and periaqueductal gray during conditioned fear, persistent pain and fear-conditioned analgesia. , 2009, The journal of pain : official journal of the American Pain Society.

[39]  V. Molina,et al.  Gabaergic modulation of the stress response in frontal cortex and amygdala , 2002, Synapse.

[40]  O. Stork,et al.  Disruption of fear memory consolidation and reconsolidation by actin filament arrest in the basolateral amygdala , 2010, Neurobiology of Learning and Memory.

[41]  G. Richter-Levin,et al.  Exposure to Stressors during Juvenility Disrupts Development-Related Alterations in the PSA-NCAM to NCAM Expression Ratio: Potential Relevance for Mood and Anxiety Disorders , 2008, Neuropsychopharmacology.

[42]  H. Xue,et al.  GABAergic functions and depression: from classical therapies to herbal medicine. , 2003, Current drug targets. CNS and neurological disorders.

[43]  K. Rosenblum,et al.  Juvenile stress-induced alteration of maturation of the GABAA receptor alpha subunit in the rat. , 2008, The international journal of neuropsychopharmacology.

[44]  Y. Peterschmitt,et al.  Altered GABA transmission in a mouse model of increased trait anxiety , 2011, Neuroscience.

[45]  Abraham Weizman,et al.  Effects of early-life stress on behavior and neurosteroid levels in the rat hypothalamus and entorhinal cortex , 2006, Brain Research Bulletin.

[46]  F. Holsboer,et al.  Long-Lasting Hippocampal Synaptic Protein Loss in a Mouse Model of Posttraumatic Stress Disorder , 2012, PloS one.

[47]  Y. Yovell,et al.  A rat model of pre-puberty (Juvenile) stress-induced predisposition to stress-related disorders: Sex similarities and sex differences in effects and symptoms , 2014, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[48]  V. Molina,et al.  Previous Stress Facilitates Fear Memory, Attenuates GABAergic Inhibition, and Increases Synaptic Plasticity in the Rat Basolateral Amygdala , 2005, The Journal of Neuroscience.

[49]  J. Feldon,et al.  Nonphysical contact between cagemates alleviates the social isolation syndrome in C57BL/6 male mice. , 2008, Behavioral neuroscience.

[50]  J. Harro,et al.  Increased Vulnerability to Depressive-Like Behavior of Mice with Decreased Expression of VGLUT1 , 2009, Biological Psychiatry.

[51]  K. Obata,et al.  Recovery of emotional behaviour in neural cell adhesion molecule (NCAM) null mutant mice through transgenic expression of NCAM180 , 2000, The European journal of neuroscience.

[52]  Rajeevan T Narayanan,et al.  Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory. , 2008, Learning & memory.

[53]  J. Feldon,et al.  The postweaning social isolation in C57BL/6 mice: preferential vulnerability in the male sex , 2008, Psychopharmacology.

[54]  L. Davis,et al.  Baclofen Treatment for Chronic Posttraumatic Stress Disorder , 2003, The Annals of pharmacotherapy.

[55]  M. Geyer,et al.  Isolation rearing of mice induces deficits in prepulse inhibition of the startle response , 2006, Behavioural Brain Research.

[56]  R. D'Hooge,et al.  Nocturnal hyperactivity, increased social novelty preference and delayed extinction of fear responses in post-weaning socially isolated mice , 2011, Brain Research Bulletin.

[57]  Adem Can,et al.  The tail suspension test. , 2011, Journal of visualized experiments : JoVE.