Elsevier

Neuroscience

Volume 406, 15 May 2019, Pages 186-201
Neuroscience

Research Article
Role of CX3CR1 Signaling on the Maturation of GABAergic Transmission and Neuronal Network Activity in the Neonate Hippocampus

https://doi.org/10.1016/j.neuroscience.2019.03.006Get rights and content

Highlights

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    CX3CR1 deficiency only marginally affects hippocampal GABAergic currents during the first two post-natal weeks.

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    Fractalkine signaling deficiency does not impact the postnatal maturation of GABAergic transmission.

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    The frequency of GDPs is drastically reduced in CX3CR1 deficient mice during the first postnatal week.

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    Adults CX3CR1 deficient mice have no behavioral deficits in sensory gating information (PPI).

Abstract

In the developing brain, microglial cells play an important role in shaping neuronal circuits. These immune cells communicate with neurons through fractalkine (CX3CL1), a neuronal cytokine that acts on microglial CX3CR1 receptor. Among various functions, this signaling pathway has been implicated in the postnatal maturation of glutamatergic synapses. Although microglial cells are present in the neonate hippocampus when GABA receptor-mediated synaptic transmission and synchronized oscillatory events take place, it remains unknown whether microglial cells tune the establishment of these activities. Using CX3CR1-deficient mice and electrophysiological means, we investigated in CA3 pyramidal neurons the role of the fractalkine signaling in the maturation of GABAA receptor-mediated synaptic currents and giant depolarizing potentials (GDPs), a network activity important for shaping synaptic connections. In CX3CR1-deficient mice, GABAergic currents were slightly altered, whereas the developmental changes of these currents were comparable with wild-type animals. Despite these minor changes in GABAergic transmission, the GDP frequency was strikingly reduced in CX3CR1-deficient mice compared to wild-type, with no change in the GDP shape and ending period. Collectively, it emerges that, in the neonate hippocampus, the fractalkine signaling pathway tunes GDP activities and is marginally involved in the maturation of GABAergic synapses, suggesting that microglial cells have distinct impact on maturing GABAergic, glutamatergic, and network functions.

Section snippets

INTRODUCTION

Microglia are the predominant immunocompetent cells of the central nervous system (CNS), where they act as phagocytes. In addition to their roles in pathological conditions, physiological functions in brain development, plasticity and cognition have recently gained support (Tay et al., 2017b). Unlike other cell types in the CNS parenchyma, microglia have a myeloid origin, as they derive from primitive macrophages in the yolk sac. In rodents, they colonize the CNS parenchyma in successive waves,

Animals

All experimental procedures followed the guidelines of the University of Bordeaux/Centre National de la Recherche Scientifique Animal Care and Use Committee. Female and male mice from postnatal day 2 (P2) to 16 (P16) were used in the study (total number of animal 121). However, whenever possible females were used for electrophysiological experiments, while only males were used for behavioral experiments. In all the experiments performed after P7, pups were obtained by crossing two N6 CX3CR1

Lower microglial density in the hippocampus of CX3CR1eGFP/eGFP mice

Microglia density in the hippocampus of young CX3CR1eGFP/eGFP mice is reduced when compared to heterozygous mice (Paolicelli et al., 2011), whereas their sub-regional distribution, but not their total density, is affected in the barrel cortex (Hoshiko et al., 2012). We thus used Iba1 staining to measure the microglia density in WT and CX3CR1eGFP/eGFP mice in different hippocampal sub-regions in the neonate hippocampus: the stratum oriens and the stratum radiatum of CA1 and CA3 areas. To collect

DISCUSSION

A proper interplay between neurons and microglia is essential for the establishment and maturation of synaptic networks in the developing brain (Schafer et al., 2013, Sierra et al., 2014). Alterations of this interaction lead to adult brain plasticity and behavioral deficits that have been associated with neuropsychiatric diseases. Here, we show that during the postnatal period a deficiency in the fractalkine pathway leads to a reduced number of microglia and GDP network activity, whereas the

Author Contributions

EA and LG conceived the study; CB, EA and LG designed the experiments; CB and EA performed experiments and statistical analysis; EA, CB, and LG interpreted the data; EA, LG, and CB wrote and revised the manuscript.

Funding

CB was a recipient of PhD grant from the Ministère de l'Enseignement Supérieur et de la Recherche. This work was supported by the Centre National de la Recherche Scientifique, Université de Bordeaux, Fondation pour la Recherche Médicale, Conseil Régional d'Aquitaine, Labex Bordeaux BRAIN.

Acknowledgments

We thank Emily M. Johansson for technical assistance on PPI experiments, Pascal Branchereau for his contribution to the KCC2 data, and M. Goillandeau for providing the program Mini Analysis. We thank Anne Roumier for providing CX3CR1 mice, Pierre Costet and Elena Morillon for taking care of the animals. This work benefited from the support of the Genotyping and Transcriptomic facilities funded by Inserm and LabEX BRAIN ANR-10-LABX-43, special thanks to D. Gonzales and T. Leste-Lasserre. We also

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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