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Genetic deletion of P-glycoprotein alters stress responsivity and increases depression-like behavior, social withdrawal and microglial activation in the hippocampus of female mice.
Brzozowska, Natalia I; Smith, Kristie L; Zhou, Cilla; Waters, Peter M; Cavalcante, Ligia Menezes; Abelev, Sarah V; Kuligowski, Michael; Clarke, David J; Todd, Stephanie M; Arnold, Jonathon C.
Afiliación
  • Brzozowska NI; Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia; The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
  • Smith KL; Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia; The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
  • Zhou C; Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia; The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
  • Waters PM; Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia.
  • Cavalcante LM; Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia; The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
  • Abelev SV; Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia; The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
  • Kuligowski M; The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia; Australian Microscopy & Microanalysis Research Facility, University of Sydney, Camperdown, NSW, Australia.
  • Clarke DJ; Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia; The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
  • Todd SM; Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia; The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
  • Arnold JC; Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia; The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia. Electronic address: jonathon.arnold@sydney.edu.au.
Brain Behav Immun ; 65: 251-261, 2017 Oct.
Article en En | MEDLINE | ID: mdl-28502879
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Estrés Psicológico / Receptores de Glucocorticoides / Miembro 1 de la Subfamilia B de Casetes de Unión a ATP Límite: Animals Idioma: En Revista: Brain Behav Immun Asunto de la revista: ALERGIA E IMUNOLOGIA / CEREBRO / PSICOFISIOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Estrés Psicológico / Receptores de Glucocorticoides / Miembro 1 de la Subfamilia B de Casetes de Unión a ATP Límite: Animals Idioma: En Revista: Brain Behav Immun Asunto de la revista: ALERGIA E IMUNOLOGIA / CEREBRO / PSICOFISIOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Países Bajos