Microglia‐derived purines modulate mossy fibre synaptic transmission and plasticity through P2X₄ and A₁ receptors

Abstract

Recent data have provided evidence that microglia, the brain-resident macrophage-like cells, modulate neuronal activity in both physiological and pathophysiological conditions, and microglia are therefore now recognized as synaptic partners. Among different neuromodulators, purines, which are produced and released by microglia, have emerged as promising candidates to mediate interactions between microglia and synapses. The cellular effects of purines are mediated through a large family of receptors for adenosine and for ATP (P2 receptors). These receptors are present at brain synapses, but it is unknown whether they can respond to microglia-derived purines to modulate synaptic transmission and plasticity. Here, we used a simple model of adding immune-challenged microglia to mouse hippocampal slices to investigate their impact on synaptic transmission and plasticity at hippocampal mossy fibre (MF) synapses onto CA3 pyramidal neurons. MF-CA3 synapses show prominent forms of presynaptic plasticity that are involved in the encoding and retrieval of memory. We demonstrate that microglia-derived ATP differentially modulates synaptic transmission and short-term plasticity at MF-CA3 synapses by acting, respectively, on presynaptic P2X 4 receptors and on adenosine A 1 receptors after conversion of extracellular ATP to adenosine. We also report that P2X 4 receptors are densely located in the mossy fibre tract in the dentate gyrus-CA3 circuitry. In conclusion, this study reveals an interplay between microglia-derived purines and MF-CA3 synapses, and highlights microglia as potent modulators of presynaptic plasticity.

How does adenosine control neuronal dysfunction and neurodegeneration?

“…ATP can also be released through multiple other pathways (Hamann and Attwell 1996;Lazarowski 2012;Orellana et al 2013;Oya et al 2013;Zhang et al 2007a;reviewed in Bodin and Burnstock 2001) from different cell types, namely terminals, dendrites, and axons from neurons (White 1978;Pankratov et al 2006Pankratov et al , 2007Zhang et al 2007b;Fields 2011a,b;Lovatt et al 2012), astrocytes (Newman 2003;Halassa et al 2009;Koizumi 2010) and microglia (Dou et al 2012;Imura et al 2013;George et al 2015). This is in accordance with the multiple physiological roles that have been ascribed to extracellular ATP (reviewed in Rodrigues et al 2015): (i) ATP can act as a neurotransmitter, as heralded by the P2X receptor-mediated ATPergic transmission described in brain circuits (Edwards et al 1992;Bardoni et al 1997;Nieber et al 1997;Pankratov et al 1999Pankratov et al , 2002Mori et al 2001); (ii) ATP is also a controller of inflammation (reviewed in Di et al 2009;Idzko et al 2014), with multiple actions on microglia (reviewed in Koizumi et al 2013) impacting on the function of astrocytes and neuronal networks (Pascual et al 2012;George et al 2016); (iii) ATP and adenosine both regulate oligodendrocyte differentiation and myelination (Agresti et al 2005) in an activity-dependent manner (Fields 2006); (iv) ATP is a paracrine modulator of astrocytes and a neuron-or microglia-to-astrocyte signal by sustaining Ca 2+ -waves, the main mechanism to propagate glial excitability and intercellular communication (Guthrie et al 1999;...…”

“…; George et al . ); (iii) ATP and adenosine both regulate oligodendrocyte differentiation and myelination (Agresti et al . ) in an activity‐dependent manner (Fields ); (iv) ATP is a paracrine modulator of astrocytes and a neuron‐ or microglia‐to‐astrocyte signal by sustaining Ca 2+ ‐waves, the main mechanism to propagate glial excitability and intercellular communication (Guthrie et al .…”

“…; George et al . ); (vii) as an endothelial modulator, controlling the vasodilation of brain capillaries (O'Regan ; Ohata et al . ; Kusano et al .…”

Disruption of theATP/adenosine balance inCD39−/−mice is associated with handling‐induced seizures

“…also recently showed that CD39 −/− microglia had attenuated ramification, a phenotype that has been correlated with microglia quiescence. Interestingly, microglia‐derived ATP and adenosine mediate synaptic plasticity and transmission and microglia‐dependent modulation of neuronal activity has been shown to depend on neuronal hemi‐channels, channels important for ATP release. Therefore, our findings do not rule out the possibility that CD39 −/− mice may have altered neuron–microglia communication that could contribute to the observed seizure phenotype.…”

Adenosine A1 Receptor mRNA Expression by Neurons and Glia in the Auditory Forebrain

“…In oligodendrocytes, A 1 Rs promote myelination during axonal maturation (Stevens et al, ), and contribute to white matter loss in pathology (Kim et al, ). In microglia, A 1 R activation on microglia can regulate proliferation (Haselkorn et al, ), limit the inflammatory response (Tsutsui et al, ), contribute to the neuroprotective effects associated with adenosine delivery (Lauro et al, ; Pedata et al, ), and modulate short‐term synaptic transmission and plasticity (George et al, ). Many other functions are mediated by purinergic signaling through other receptors and pathways, as well.…”