The Safeguarding Microglia: Central Role for P2Y12 Receptors

Lin, Si-Si; Tang, Yong; Illéš, Peter; Verkhratsky, Alexei

doi:10.3389/fphar.2020.627760

Cited by 25 publications

(27 citation statements)

References 66 publications

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“…Thus, a great deal of previous research about P2Y12R gene polymorphisms focused on platelet aggregation or pharmacological response to anti-platelet drugs [35][36][37][38]. Nevertheless, recent studies demonstrated that the P2Y12R is expressed and functional in microglial cells [39,40],Gómez et al, 2021, [41]. Microglial P2Y12R detects the synaptic release of ATP after neuronal activity and controls chemotaxis and motility of microglia, which are involved in microglia-mediated suppression of neuronal activities [14,15,28,29,42].…”

Section: Discussionmentioning

confidence: 99%

P2Y12 receptor gene polymorphisms are associated with epilepsy

Wang

Shi

et al. 2022

Purinergic Signalling

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The basic research indicated that microglial P2Y12 receptors (P2Y12Rs) are involved in the pathophysiology of epilepsy through regulated microglial-neuronal interactions, aberrant neurogenesis, or immature neuronal projections. However, whether the clinic case of epilepsy would be associated with P2Y12 receptor gene polymorphisms is presented with few data. In our study, a total of 176 patients with epilepsy and 50 healthy controls were enrolled. Two single-nucleotide polymorphisms, namely rs1491974 and rs6798347, were selected for analysis. The results revealed that carriers of the G allele of rs1491974 G>A or rs6798347 G>A may be associated with an increased risk of epilepsy (OR = 0.576, 95% CI = 0.368–0.901, p = 0.015; OR = 0.603, 95% CI = 0.367–0.988, p = 0.043). Interestingly, we found that the rs1491974 G>A genotype and allele frequencies have only a significant difference in female instead of male case (p = 0.004 for genotype; p = 0.001 for allele). The subgroup analysis demonstrated that individuals with the rs1491974 G>A genotype might have more frequent seizure (OR = 0.476, 95% CI = 0.255–0.890; p = 0.019). These data implied that both rs1491974 and rs6798347 polymorphisms of P2Y12R would be able to play import roles in epilepsy susceptibility, whereas the rs1491974 polymorphism may be specifically related to seizure frequency.

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Section: Discussionmentioning

confidence: 99%

P2Y12 receptor gene polymorphisms are associated with epilepsy

Wang

Shi

et al. 2022

Purinergic Signalling

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“…In the retina, for example, microglial surveillance is increased by stimulation of ionotropic glutamate receptors and decreased when γ‐aminobutyric acid A (GABA A ) receptors are activated (Fontainhas et al ., 2011). Throughout the CNS, physiological microglial plasticity is controlled by purinergic signalling, with a particular role for P2Y 12 purinoceptors operational in microglial cells in the healthy brain (Burnstock & Verkhratsky, 2012; Calovi, Mut‐Arbona & Sperlagh, 2019; Illes et al ., 2020; Lin et al ., 2020). In many instances, however, microglial surveillance does not require ambient purinergic signalling, being associated instead with plasmalemmal channels and membrane polarisation (Madry et al ., 2018).…”

Section: Microglial Morphotypes In the Healthy Brainmentioning

confidence: 99%

“…This type of activity requires P2Y 12 purinoreceptors (Sipe et al ., 2016). The P2Y 12 purinoreceptors, localised in the processes and in the somata, control several aspects of microglial surveillance (Haynes et al ., 2006; Lin et al ., 2020). Stimulation of P2Y 12 purinoreceptors initiates hyper‐ramification and increases interaction with synapses, contributing to experience‐dependent plasticity (Sipe et al ., 2016).…”

Section: Microglial Morphotypes In the Healthy Brainmentioning

confidence: 99%

“…Emergence of this phenotype seems to be induced by phagocytosis of apoptotic neurones (Krasemann et al ., 2017). A subpopulation of microglia expressing P2Y 12 Rs (associated with a physiological, protective phenotype) has been found in several chronic neuropathologies including major depression (Bottcher et al ., 2020) and Alzheimer's disease (Walker et al ., 2020); arguably these P2Y 12 ‐positive microglia represent recovery or defensive microglia, emerging in response to neuropathology (Lin et al ., 2020). A specific subtype of recovery microglia was identified in mice experiencing severe seizures.…”

Section: Microglial Morphotypes In Pathologymentioning

confidence: 99%

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Plasticity of microglia

et al. 2021

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Microglial cells are the scions of foetal macrophages which invade the neural tube early during embryogenesis. The nervous tissue environment instigates the phenotypic metamorphosis of foetal macrophages into idiosyncratic surveilling microglia, which are generally characterised by a small cell body and highly ramified motile processes that constantly scan the nervous tissue for signs of changes in homeostasis and allow microglia to perform crucial homeostatic functions. The surveilling microglial phenotype is evolutionarily conserved from early invertebrates to humans. Despite this evolutionary conservation, microglia show substantial heterogeneity in their gene and protein expression, as well as morphological appearance. These differences are age, region and context specific and reflect a high degree of plasticity underlying the life‐long adaptation of microglia, supporting the exceptional adaptive capacity of the central nervous system. Microgliocytes are essential elements of cellular network formation and refinement in the developing nervous tissue. Several distinct patrolling modes of microglial processes contribute to the formation, modification, and pruning of synapses; to the support and protection of neurones through microglial–somatic junctions; and to the control of neuronal and axonal excitability by specific microglia–axonal contacts. In pathology, microglia undergo proliferation and reactive remodelling known as microgliosis, which is context dependent, yet represents an evolutionarily conserved defence response. Microgliosis results in the emergence of multiple disease and context‐specific reactive states; in addition, neuropathology is associated with the appearance of specific protective or recovery microglial forms. In summary, the plasticity of microglia supports the development and functional activity of healthy nervous tissue and provides highly sophisticated defences against disease.

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“…Out of several types of P2Y receptors expressed by microglia, the P2Y12 purinoceptors are of a specific importance. These receptors are expressed by surveilling microglia in the healthy nervous tissues (Haynes et al, 2006;Sasaki et al, 2003); they are concentrated in microglial processes and regulate various microglial patrolling modes (Cserep et al, 2020a;Lin et al, 2020) Besides purinoceptors microglial cells express iono-and metabotropic receptors to glutamate (Kaindl et al, 2012;Noda et al, 2000;Yamada et al, 2006), GABAB receptors (Kuhn et al, 2004), 7 acetylcholine receptors, 1A, 2A, 1 and 2 adrenoceptors (Sugama and Kakinuma, 2020), D1-4 dopamine receptors and 5-HT2 serotonin receptors (Kettenmann et al, 2011). In addition, microglia express numerous receptors to neuromodulators and neurohormones including, for example, receptors to bradykinin, ETB endothelin receptors, angiotensin receptors, somatostatin receptors, opioid receptors, and neurotrophin receptors to name but a few (Kettenmann et al, 2011).…”

Section: Microglia Physiology: Receptorsmentioning

confidence: 99%