Article

Adenosine A(2A) receptor mediates microglial process retraction. Nat Neurosci

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.
Nature Neuroscience (Impact Factor: 16.1). 08/2009; 12(7):872-8. DOI: 10.1038/nn.2341
Source: PubMed

ABSTRACT

Cell motility drives many biological processes, including immune responses and embryonic development. In the brain, microglia are immune cells that survey and scavenge brain tissue using elaborate and motile cell processes. The motility of these processes is guided by the local release of chemoattractants. However, most microglial processes retract during prolonged brain injury or disease. This hallmark of brain inflammation remains unexplained. We identified a molecular pathway in mouse and human microglia that converted ATP-driven process extension into process retraction during inflammation. This chemotactic reversal was driven by upregulation of the A(2A) adenosine receptor coincident with P2Y(12) downregulation. Thus, A(2A) receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation. Our results indicate that purine nucleotides provide an opportunity for context-dependent shifts in receptor signaling. Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation.

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Available from: ncbi.nlm.nih.gov
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    • "Adenosine seems to be a potential candidate for regulating microglial motility because high levels of adenosine receptors A1 and A3 are expressed on microglia in physiological conditions (Hammarberg et al., 2003) and an interplay of simultaneous purinergic stimulation of both A3 and P2Y12 receptors was found necessary for process outgrowth (Ohsawa et al., 2012). Adenosine was also involved in the retraction of microglial processes in the pathological brain due to signaling involving A2A receptors (Orr et al., 2009). ATP appears to be released in an activity-dependent manner by neurons and astrocytes through hemichannels (pannexin and connexin), transporters and secretory vesicles (Burnstock, 2008). "
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    ABSTRACT: Microglia, the resident immune cells of the central nervous system (CNS), were traditionally believed to be set into action only in case of injury or disease. Accordingly, microglia were assumed to be inactive or resting in the healthy brain. However, recent studies revealed that microglia carry out active tissue sampling in the intact brain by extending and retracting their ramified processes while periodically contacting synapses. Microglial morphology and motility as well as the frequency and duration of physical contacts with synaptic elements were found to be modulated by neuronal activity, sensory experience and neurotransmission; however findings have not been straightforward. Microglial cells are the most morphologically plastic element of the CNS. This unique feature confers them the possibility to locally sense activity, and to respond adequately by establishing synaptic contacts to regulate synaptic inputs by the secretion of signaling molecules. Indeed, microglial cells can hold new roles as critical players in maintaining brain homeostasis and regulating synaptic number, maturation and plasticity. For this reason, a better characterization of microglial cells and cues mediating neuron-to-microglia communication under physiological conditions may help advance our understanding of the microglial behavior and its regulation in the healthy brain. This review highlights recent findings on the instructive role of neuronal activity on microglial motility and microglia-synapse interactions, focusing on the main transmitters involved in this communication and including newly described communication at the tripartite synapse.
    Preview · Article · Jan 2016 · Frontiers in Integrative Neuroscience
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    • "Also we show that this injuryinduced microglial current was mediated by P2Y12R.Potassium channel coupled to microglial P2Y12R P2Y12R were initially identified on platelets and are responsible for platelet activation and aggregation during the blood clotting process (Hollopeter et al., 2001). The expression of P2Y12R in microglia was first described bySasaki et al. (2003)and has been implicated in microglia activation, migration, chemotaxis and phagocytic ability (Haynes et al., 2006;Wu et al., 2007;Orr et al., 2009;De Simone et al., 2010;Sunkaria et al., 2015). P2Y12R plays a vital role in microglia activation, as they act as the primary site at which nucleotides act to induce microglial chemotaxis in response to local CNS injury (Haynes et al., 2006;De Simone et al., 2010). "
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    ABSTRACT: Microglia, the resident immune cells in the central nervous system (CNS), constantly survey the surrounding neural parenchyma and promptly respond to brain injury. Activation of purinergic receptors such as P2Y12 receptors (P2Y12R) in microglia has been implicated in chemotaxis toward ATP that is released by injured neurons and astrocytes. Activation of microglial P2Y12R elicits outward potassium current that is associated with microglial chemotaxis in response to injury. This study aimed at investigating the identity of the potassium channel implicated in microglial P2Y12R-mediated chemotaxis following neuronal injury and understanding the purinergic signaling pathway coupled to the channel. Using a combination of two-photon imaging, electrophysiology and genetic tools, we found the ATP-induced outward current to be largely dependent on P2Y12R activation and mediated by G-proteins. Similarly, P2Y12R-coupled outward current was also evoked in response to laser-induced single neuron injury. This current was abolished in microglia obtained from mice lacking P2Y12R. Dissecting the properties of the P2Y12R-mediated current using a pharmacological approach revealed that both the ATP and neuronal injury-induced outward current in microglia was sensitive to quinine (1 mM) and bupivacaine (400 μM), but not tetraethylammonium (TEA) (10 mM) and 4-aminopyridine (4-AP) (5 mM). These results suggest that the quinine/bupivacaine-sensitive potassium channels are the functional effectors of the P2Y12R–mediated signaling in microglia activation following neuronal injury.
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    • "With regards to the number of cells quantified for the microglial Process Length Analysis and End Point Voxel Analysis, we used all the cells in the field of view which ranged from $40 total cells in control tissues to up to $120 cells at POD7 after SNT. These data were used as measures of microglial morphology based on previous reports showing reduced microglia process branching complexity and process length during microglial activation (Fontainhas et al., 2011; Orr et al., 2009; Stence et al., 2001). The number of cell somas per frame was used to normalise all process endpoints and process lengths. "
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    ABSTRACT: Microglial cells are critical in the pathogenesis of neuropathic pain and several microglial receptors have been proposed to mediate this process. Of these receptors, the P2Y12 receptor is a unique purinergic receptor that is exclusively expressed by microglia in the central nervous system (CNS). In this study, we set forth to investigate the role of P2Y12 receptors in microglial electrophysiological and morphological (static and dynamic) activation during spinal nerve transection (SNT)-induced neuropathic pain in mice. First, we found that a genetic deficiency of the P2Y12 receptor (P2Y12(-/-) mice) ameliorated pain hypersensitivities during the initiation phase of neuropathic pain. Next, we characterized both the electrophysiological and morphological properties of microglia in the superficial spinal cord dorsal horn following SNT injury. We show dramatic alterations including a peak at 3 days post injury in microglial electrophysiology while high resolution two-photon imaging revealed significant changes of both static and dynamic microglial morphological properties by 7 days post injury. Finally, in P2Y12(-/-) mice, these electrophysiological and morphological changes were ameliorated suggesting roles for P2Y12 receptors in SNT-induced microglial activation. Our results therefore indicate that P2Y12 receptors regulate microglial electrophysiological as well as static and dynamic microglial properties after peripheral nerve injury, suggesting that the microglial P2Y12 receptor could be a potential therapeutic target for the treatment of neuropathic pain.
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