Genetic deletion of P-glycoprotein alters stress responsivity and increases depression-like behavior, social withdrawal and microglial activation in the hippocampus of female mice
| Autor: | Kristie Leigh Smith, Cilla Zhou, Michael Kuligowski, Jonathon C. Arnold, Natalia I. Brzozowska, David J. Clarke, Ligia Menezes Cavalcante, Sarah V. Abelev, Stephanie M. Todd, Peter M. Waters |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty ATP Binding Cassette Transporter Subfamily B Immunology Hippocampus Endogeny Context (language use) Anxiety Blood–brain barrier Amygdala 03 medical and health sciences Behavioral Neuroscience Mice 0302 clinical medicine Glucocorticoid receptor Receptors Glucocorticoid Internal medicine medicine Animals ATP Binding Cassette Transporter Subfamily B Member 1 Social Behavior Mice Knockout Microglia Behavior Animal Endocrine and Autonomic Systems Depression Brain Fear Anxiety Disorders Temporal Lobe 030104 developmental biology medicine.anatomical_structure Endocrinology Blood-Brain Barrier Knockout mouse Female Psychology Neuroscience 030217 neurology & neurosurgery Stress Psychological |
| Zdroj: | Brain, behavior, and immunity. 65 |
| ISSN: | 1090-2139 |
| Popis: | P-glycoprotein (P-gp) is an ABC transporter expressed at the blood brain barrier and regulates the brain uptake of various xenobiotics and endogenous mediators including glucocorticoid hormones which are critically important to the stress response. Moreover, P-gp is expressed on microglia, the brain’s immune cells, which are activated by stressors and have an emerging role in psychiatric disorders. We therefore hypothesised that germline P-gp deletion in mice might alter the behavioral and microglial response to stressors. Female P-gp knockout mice displayed an unusual, frantic anxiety response to intraperitoneal injection stress in the light-dark test. They also tended to display reduced conditioned fear responses compared to wild-type (WT) mice in a paradigm where a single electric foot-shock stressor was paired to a context. Foot-shock stress reduced social interaction and decreased microglia cell density in the amygdala which was not varied by P-gp genotype. Independently of stressor exposure, female P-gp deficient mice displayed increased depression-like behavior, idiosyncratic darting behavior, age-related social withdrawal and hyperactivity, facilitated sensorimotor gating and altered startle reactivity. In addition, P-gp deletion increased microglia cell density in the CA3 region of the hippocampus, and the microglial cells exhibited a reactive, hypo-ramified morphology. Further, female P-gp KO mice displayed increased glucocorticoid receptor (GR) expression in the hippocampus. In conclusion, this research shows that germline P-gp deletion affected various behaviors of relevance to psychiatric conditions, and that altered microglial cell activity and enhanced GR expression in the hippocampus may play a role in mediating these behaviors. |
| Databáze: | OpenAIRE |
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