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Microglial cells, the resident macrophages of the central nervous system (CNS), exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell-damaging factors, they get transformed into an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species, and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia have a number of important physiological functions in the CNS; for example, they shield small disruptions of the blood-brain barrier by their processes, dynamically interact with synaptic structures, and clear surplus synapses during development. In neurodegenerative illnesses, they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction. Therefore, the blockade of this reaction improves the outcome of Alzheimer's Disease, Parkinson's Disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. The function of microglia is regulated by a whole array of purinergic receptors classified as P2Y12, P2Y6, P2Y4, P2X4, P2X7, A2A, and A3, as targets of endogenous ATP, ADP, or adenosine. ATP is sequentially degraded by the ecto-nucleotidases and 5'-nucleotidase enzymes to the almost inactive inosine as an end product. The appropriate selective agonists/antagonists for purinergic receptors as well as the respective enzyme inhibitors may profoundly interfere with microglial functions and reconstitute the homeostasis of the CNS disturbed by neuroinflammation., Competing Interests: All authors declare no conflicts of interest.

There is ongoing dispute on the question whether CNS neurons possess ATP-sensitive P2X7 receptors (Rs) or whether only non-neuronal cells bear this receptor-type and indirectly signal to the neighboring neurons. We genetically deleted P2X7Rs specifically in astrocytes, oligodendrocytes and microglia, and then recorded current responses in neurons to the prototypic agonist of this receptor, dibenzoyl-ATP (Bz-ATP). These experiments were made in brain slice preparations taken from the indicated variants of the P2X7R KO animals. In hippocampal CA3, but not CA1 pyramidal neurons, the deletion of oligodendrocytic (NG2 glial) P2X7Rs abolished the Bz-ATP-induced current responses. In contrast to the Bz-ATP-induced currents in CA3 pyramidal neurons, current amplitudes evoked by the ionotropic glutamate/GABAAR agonists AMPA/muscimol were not inhibited at all. Whereas in the CA3 area NG2 glia appeared to mediate the P2X7R-mediated stimulation of pyramidal neurons, in the CA1 area, astrocytic P2X7Rs had a somewhat similar effect. This was shown by recording the frequencies and amplitudes of spontaneous excitatory currents (sPSCs) in brain slice preparations. Bz-ATP increased the sPSC frequency in CA1, but not CA3 pyramidal neurons without altering the amplitude, indicating a P2X7R-mediated increase of the neuronal input. Microinjection of the selective astrocytic toxin L-α-aminoadipate into both hippocampi, or the in vitro application of the GABAAR antagonistic gabazine, completely blocked the frequency increases of sPSCs. Hence, CA1 and CA3 pyramidal neurons of the mouse did not possess P2X7Rs, but were indirectly modulated by astrocytic and oligodendrocytic P2X7Rs, respectively. [ABSTRACT FROM AUTHOR]

The mood disorders, major depression (MD) and bipolar disorder (BD), have a high lifetime prevalence in the human population and accordingly generate huge costs for health care. Efficient, rapidly acting, and side-effect-free pharmaceuticals are hitherto not available, and therefore, the identification of new therapeutic targets is an imperative task for (pre)clinical research. Such a target may be the purinergic P2X7 receptor (P2X7R), which is localized in the central nervous system (CNS) at microglial and neuroglial cells mediating neuroinflammation. MD and BD are due to neuroinflammation caused in the first line by the release of the pro-inflammatory cytokine interleukin-1β (IL-1β) from the microglia. IL-1β in turn induces the secretion of corticotropin-releasing hormone (CRH) and in consequence the secretion of adrenocorticotropic hormone (ACTH) and cortisol, which together with a plethora of further cytokines/chemokines lead to mood disorders. A number of biochemical/molecular biological measurements including the use of P2X7R- or IL-1β-deficient mice confirmed this chain of events. More recent studies showed that a decrease in the astrocytic release of ATP in the prefrontal cortex and hippocampus is a major cause of mood disorders. It is an attractive hypothesis that compensatory increases in P2X7Rs in these areas of the brain are the immediate actuators of MD and BD. Hence, blood-brain barrier-permeable P2X7R antagonists may be promising therapeutic tools to improve depressive disorders in humans. [ABSTRACT FROM AUTHOR]

P2X7 receptors (Rs) constitute a subclass of ATP-sensitive ionotropic receptors (P2X1-P2X7). P2X7Rs have many distinguishing features, mostly based on their long intracellular C terminus regulating trafficking to the cell membrane, protein-protein interactions, and post-translational modification. Their C-terminal tail is especially important in enabling the transition from the nonselective ion channel mode to a membrane pore allowing the passage of large molecules. There is an ongoing dispute on the existence of neuronal P2X7Rs with consequences for our knowledge on their involvement in neuroinflammation, aggravating stroke, temporal lobe epilepsy, neuropathic pain, and various neurodegenerative diseases. Whereas early results appeared to support the operation of P2X7Rs at neurons, more recently glial P2X7Rs are increasingly considered as indirect causes of neuronal effects. Specific tools for P2X7Rs are of limited value because of the poor selectivity of agonists, and the inherent failure of antibodies to differentiate between the large number of active and inactive splice variants, or gain-of-function and loss-of-function small nucleotide polymorphisms of the receptor. Unfortunately, the available P2RX7 knock-out mice generated by pharmaceutical companies possess certain splice variants, which evade inactivation. In view of the recently discovered bidirectional dialogue between astrocytes and neurons (and even microglia and neurons), we offer an alternative explanation for previous data, which assumedly support the existence of P2X7Rs at neurons. We think that the unbiased reader will follow our argumentation on astrocytic or microglial P2X7Rs being the primary targets of pathologically high extracellular ATP concentrations, although a neuronal localization of these receptors cannot be fully excluded either. [ABSTRACT FROM AUTHOR]

Neuroglia, represented by astrocytes, oligodendrocytes, NG glia and microglia are homeostatic, myelinating and defensive cells of the brain. Neuroglial cells express various combinations of purinoceptors, which contribute to multiple intercellular signalling pathways in the healthy and diseased nervous system. Neurological diseases are invariably associated with profound neuroglial remodelling, which is manifest by reactive gliosis, pathological remodelling and functional atrophy of various types of glial cells. Gliopathology is disease and region specific and produces multiple glial phenotypes that may be neuroprotective or neurotoxic. In this review we summarise recent knowledge on the role of glial purinergic signalling in cognitive-related neurological diseases. This article is part of the Special Issue entitled ‘Purines in Neurodegeneration and Neuroregeneration’. [ABSTRACT FROM AUTHOR]

Extracellular adenosine 5′-triphosphate (ATP) in the brain is suggested to be an etiological factor of major depressive disorder (MDD). It has been assumed that stress-released ATP stimulates P2X7 receptors (Rs) at the microglia, thereby causing neuroinflammation; however, other central nervous system (CNS) cell types such as astrocytes also possess P2X7Rs. In order to elucidate the possible involvement of the MDD-relevant hippocampal astrocytes in the development of a depressive-like state, we used various behavioral tests (tail suspension test [TST], forced swim test [FST], restraint stress, inescapable foot shock, unpredictable chronic mild stress [UCMS]), as well as fluorescence immunohistochemistry, and patch-clamp electrophysiology in wild-type (WT) and genetically manipulated rodents. The TST and FST resulted in learned helplessness manifested as a prolongation of the immobility time, while inescapable foot shock caused lower sucrose consumption as a sign of anhedonia. We confirmed the participation of P2X7Rs in the development of the depressive-like behaviors in all forms of acute (TST, FST, foot shock) and chronic stress (UCMS) in the rodent models used. Further, pharmacological agonists and antagonists acted in a different manner in rats and mice due to their diverse potencies at the respective receptor orthologs. In hippocampal slices of mice and rats, only foot shock increased the current responses to locally applied dibenzoyl-ATP (Bz-ATP) in CA1 astrocytes; in contrast, TST and restraint depressed these responses. Following stressful stimuli, immunohistochemistry demonstrated an increased co-localization of P2X7Rs with a microglial marker, but no change in co-localization with an astroglial marker. Pharmacological damage to the microglia and astroglia has proven the significance of the microglia for mediating all types of depression-like behavioral reactions, while the astroglia participated only in reactions induced by strong stressors, such as foot shock. Because, in addition to acute stressors, their chronic counterparts induce a depressive-like state in rodents via P2X7R activation, we suggest that our data may have relevance for the etiology of MDD in humans. [ABSTRACT FROM AUTHOR]

Altered extracellular ATP hydrolysis, due to changes in ectonucleotidase activity, leads to accumulation of ATP in the endometriosis microenvironment and activates pain-inducing P2X3Rs at sensory neurons. Extracellular ATP or its enzymatic breakdown products, ADP, AMP, and adenosine, may then stimulate a range of membrane receptors (Rs). ATP is stored in millimolar concentrations within the intracellular medium but may be released to extracellular sites either through the damaged plasma membrane or by means of various transporters. [Extracted from the article]

Keywords: microglia; P2Y12 receptors; neurone-microglial crosstalk; purinergic signalling; neuroprotective EN microglia P2Y12 receptors neurone-microglial crosstalk purinergic signalling neuroprotective N.PAG N.PAG 1 01/18/21 20210114 NES 210114 Introduction The brain is the most complex organ of human body composed of several highly specialised and heterogeneous population of cells, represented by neurones, neuroglia (astrocytes, microglia, oligodendrocytes) and cells of brain vasculature. Second, in the healthy brain P2Y SB 12 sb receptors are universally and specifically expressed in microglia in all brain regions and across different species from rodents to humans ([43]; [34]); the P2Y SB 12 sb receptors are widely considered to be a signature of microglia in the healthy brain ([26]; [9]; [40]). The microglia process-neuronal somata contacts (defined as somatic microglial junctions) last for tens of minutes and even up to 1 h, which is much longer compared to microglia-dendritic or microglia-synaptic contacts which usually last for several minutes only ([13]). The P2Y SB 12 sb receptors control formation of microglia-somatic junctions, as pharmacological blockade of these receptors halves the duration of microglia-somatic contacts. [Extracted from the article]

Highlights: [•] VTA/SN-PFC organotypic co-cultures show cellular-specific susceptibility to OGD. [•] Neurons are mostly affected in parallel with a marked microglial activation. [•] The P2 antagonist PPADS and valproic acid protect organotypic cultures from OGD. [ABSTRACT FROM AUTHOR]

Abstract: P2X7 receptors are ligand-gated ion channels, expressed as homo-oligomeric assemblies of individual subunits. They are widely distributed at immunocompetent cells of the central and peripheral nervous system and are believed to be primarily involved in host-defense reaction. However, a growing amount of evidence indicates that their signaling role in the brain is more widespread than previously anticipated. In this paper, we review the present knowledge on the structural and pharmacological features of the P2X7 receptor, as well as its cell-type specific localization in the nervous system. Subsequently, the participation of P2X7 receptors in distinct neuronal, astroglial and microglial functions are described. Finally, since they may play a prominent role in certain neurologic disorders, such as ischemia-reperfusion injury, Alzheimer''s disease, spinal cord injury and sensory neuropathies, the pathological role and potential therapeutic exploitation of P2X7 receptors are also discussed. [Copyright &y& Elsevier]

The brain immune system, which consists mainly of astrocytes, microglia and infiltrating immune cells, is quiescent normally, but it is activated in response to pathophysiological events such as ischemia, trauma, inflammation and infection. Adenosine is an endogenous purine nucleoside that is generated at sites that are subjected to these ‘stressful’ conditions. Adenosine interacts with specific G-protein-coupled receptors on astrocytes, microglia and infiltrating immune cells to regulate the function of the immune system in the brain. Although many of the effects of adenosine on immune-competent cells in the brain protect neuronal integrity, adenosine might also aggravate neuronal injury by promoting inflammatory processes. A more complete understanding of adenosine receptor function in the brain immune system should help develop novel therapeutic ways to treat brain disorders that are associated with a dysfunctional immune response. [Copyright &y& Elsevier]