Abstract
Microglial cells participate in brain development and influence neuronal loss and synaptic maturation. Fractalkine is an important neuronal chemokine whose expression increases during development and that can influence microglia function via the fractalkine receptor, CX3CR1. Mice lacking Cx3cr1 show a variety of neuronal defects thought to be the result of deficient microglia function. Activation of CX3CR1 is important for the proper migration of microglia to sites of injury and into the brain during development. However, little is known about how fractalkine modulates microglial properties during development. Here we examined microglial morphology, response to ATP, and K+ current properties in acute brain slices from Cx3cr1 knockout mice across postnatal hippocampal development. We found that fractalkine signaling is necessary for the development of several morphological and physiological features of microglia. Specifically, we found that the occurrence of an outward rectifying K+ current, typical of activated microglia, that peaked during the second and third postnatal week, was reduced in Cx3cr1 knockout mice. Fractalkine signaling also influenced microglial morphology and ability to extend processes in response to ATP following its focal application to the slice. Our results reveal the developmental profile of several morphological and physiological properties of microglia and demonstrate that these processes are modulated by fractalkine signaling.
Highlights
Microglia, traditionally known as resident immune cells in the central nervous system (CNS), play essential roles in brain circuit maturation during development, participating in the precise refinement of synaptic connections (Tremblay et al, 2010; Paolicelli et al, 2011; Schafer et al, 2012; Defective microglia in Cx3cr1 knockoutZhan et al, 2014)
In order to better understand the role of fractalkine signaling in microglia physiology and its possible impact on brain development, we studied several functional properties of microglia in acute brain slices from Cx3cr1 knockout mice across the first postnatal weeks (PNWs)
Lack of Fractalkine Signaling Impairs Microglial Expression of Voltage-Dependent K+ Currents in the Second Postnatal Week We analyzed the electrophysiological properties of microglial cells by whole-cell recordings in CA1 stratum radiatum of acute hippocampal slices from Cx3cr1+/GFP and Cx3cr1GFP/GFP mice, during PNW 2
Summary
Traditionally known as resident immune cells in the central nervous system (CNS), play essential roles in brain circuit maturation during development, participating in the precise refinement of synaptic connections (Tremblay et al, 2010; Paolicelli et al, 2011; Schafer et al, 2012; Defective microglia in Cx3cr knockoutZhan et al, 2014). Microglial processes continuously sample the extracellular space and contact pre- and post-synaptic elements (Davalos et al, 2005; Nimmerjahn et al, 2005; Wake et al, 2009; Tremblay et al, 2010). Among the functional consequences of this active and continuous surveillance of the developing brain appear to be the shaping neuronal circuits by phagocytosis (Paolicelli et al, 2011) and favoring synaptic maturation (Hoshiko et al, 2012). Microglial processes rapidly rearrange toward the site of injury (Nimmerjahn et al, 2005; Lee et al, 2008). To reach the site of activating stimuli, microglia retract their cellular processes and rearrange them in a directional manner toward the lesion. Microglia activation is no longer considered an all or none event, but rather a sequence of progressive stages (Ponomarev et al, 2007; Olah et al, 2012; Crain et al, 2013) depending on the balance between pro-inflammatory and anti-inflammatory signals in the surrounding environment (Biber et al, 2007; Lively and Schlichter, 2013)
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