title: Paradoxical effects of minocycline in the developing mouse somatosensory cortex.
abstract: Minocycline, a tetracycline derivative, is known to exert neuroprotective effects unrelated to its antimicrobial action. In particular, minocycline prevents microglial activation in pathological conditions and consequently reduces the production of proinflammatory factors contributing to the propagation of diseases. Accumulative evidence indicates that microglial cells contribute to the maturation of neuronal and synaptic networks during the normal development of the central nervous system (CNS) and that perinatal inflammation is a known risk factor for brain lesions. Although minocycline has been used to infer microglia functions during development, mechanisms by which this tetracycline derivative affect the immature CNS have not been analyzed in detail. In this study, we demonstrate that minocycline administration during the first postnatal week of development has paradoxical effects on microglia phenotype and on neuronal survival in the mouse somatosensory cortex. Using a combination of immunohistochemistry and electrophysiology, we show that intraperitoneal injections of minocycline between postnatal days 6 and 8 affect distribution, morphology, and functional properties of microglia cells of the whisker-related barrel cortex, leading to the development of a phenotype resembling that of microglia activated in pathological conditions. Minocyline also induced a massive cell death that developed faster than changes in microglia phenotype, suggesting that the latter is a consequence of the former. Finally, cell death and microglial activation were not observed when minocycline treatment was postponed by only 2 days (i.e., between postnatal days 8 and 10). These observations call into question the use of tetracycline derivatives during CNS development to study microglia or to reduce perinatal inflammation.
authors.affiliation: INSERM U603, Paris, France; CNRS UMR 8154, Paris, France; Paris Descartes University, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnoux
authors.forename: Maki
authors.initials: M
authors.lastname: Hoshiko
authors.forename: Alvaro
authors.initials: A
authors.lastname: Sanz Diez
authors.forename: Etienne
authors.initials: E
authors.lastname: Audinat
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D037502:Galectin 3 / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D019394:Ki-67 Antigen / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D013003:Somatosensory Cortex / Q000166:cytology* / Q000187:drug effects* / Q000254:growth & development*; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D066127:White Matter / Q000166:cytology / Q000187:drug effects
chemical_list: C491049:Aif1 protein, mouse; D015703:Antigens, CD; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; C471885:Cx3cr1 protein, mouse; D037502:Galectin 3; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D019707:Receptors, Chemokine; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D049452:Green Fluorescent Proteins; D053148:Caspase 3; D008911:Minocycline
keywords: apoptosis; microglial activation; neuroinflammation; postnatal; potassium channels