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Neonatal proinflammatory challenge evokes a microglial response and affects the ratio between subtypes of GABAergic interneurons in the hippocampus of juvenile rats: sex-dependent and sex-independent effects

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Neonatal proinflammatory challenge (NPC) may contribute to the development of psychiatric disorders in adults. A double exposure of neonatal rats to lipopolysaccharide, a component of cellular wall of gram-negative bacteria, on postnatal days 3 and 5 provokes the development of depressive- and anxiety-like behaviors. NPC impairs neuroplasticity and cognition in adult animals, significant modifications of neuroplasticity being evident even in adolescence. We studied effects of NPC on microglia and GABAergic neuronal population of the dorsal hippocampus in juvenile male and female rats using immunofluorescent histochemistry. The expression of glutamic acid decarboxylase-67 (GAD67) and calcium-binding proteins calretinin, calbindin, and parvalbumin were used as quantitative markers of GABAergic interneurons and their specific subpopulations, respectively. NPC induced changes of microglial morphology indicating inflammatory activation mostly expressed in CA3 field; the effect was similar in males and females. The number of GAD67 expressing neurons was similar in the dorsal hippocampus of females and males independently on the NPC. The portion of calbindin-immunoreactive GAD67-positive neurons significantly increased while the portion of calretinin-immunoreactive GAD67-positive neurons significantly decreased in the CA1 field of rats exposed to NPC independently on their sex. NPC did not affect the parvalbumin-positive subpopulation of GABAergic neurons in the hippocampus of rats of either sex. These data suggest that NPC-induced modification of GABAergic neuronal population composition under the proinflammatory conditions is involved in the maintenance of excitation/inhibition homeostatic balance in the hippocampus.

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This study was supported by the Russian Science Foundation (project #19-75-00063).

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Authors and Affiliations



M. Stepanichev and N. Gulyaeva planned the experiments, conceptualized the data, analyzed the data, and wrote the manuscript. T. Goryakina, N. Lazareva, and A. Manolova performed immunnohistochemistry, fluorescent microscopy, image analysis, cell counting, and formal analysis. M. Stepanichev, A. Kvichansky, and A. Manolova performed experiments with animals. A. Kvichansky, L. Tretyakova, and M. Volobueva performed PCR analysis. A. Manolova funding acquisition.

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Correspondence to Mikhail Yu Stepanichev.

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This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. Experiments were performed in accordance with the principles of Basel declaration and Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes, and the Order of the Ministry of Health Care of the Russian Federation no. 199n, April 1, 2016 “On approval of the rules of good laboratory practice”, and were supervised by the Ethical Commission of the Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia.

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Stepanichev, M.Y., Goryakina, T., Manolova, A. et al. Neonatal proinflammatory challenge evokes a microglial response and affects the ratio between subtypes of GABAergic interneurons in the hippocampus of juvenile rats: sex-dependent and sex-independent effects. Brain Struct Funct 226, 563–574 (2021).

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