P2X&lt;sub&gt;7&lt;/sub&gt; receptor in the hippocampus is involved in gp120-induced cognitive dysfunction

Liu, Y.; Chen, G.Q.; Liu, B.Y.; Chen, Q.; Qian, Yanning; Qin, Shanshan; Liu, C.L.; Xu, Chang

doi:10.4238/gmr16019356

Cited by 10 publications

(8 citation statements)

References 36 publications

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“…Supporting this observation, status epilepticus (prolonged seizures) increased levels of P2X7 in the granule neurons of the dentate gyrus, and antagonizing the receptor reduced both seizure duration and subsequent neuronal death . P2X7 receptors have also been associated with numerous neurodegenerative diseases including Alzheimer's disease , Multiple Sclerosis , age‐related macular degeneration , and were shown to be significantly increased in the hippocampus of rats suffering from cognitive dysfunction . Subsequently, the neuroprotective effects of P2X7 antagonists have led to drug candidate studies .…”

Section: Discussionmentioning

confidence: 91%

P2X7 Receptors Regulate Phagocytosis and Proliferation in Adult Hippocampal and SVZ Neural Progenitor Cells: Implications for Inflammation in Neurogenesis

et al. 2018

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Identifying the signaling mechanisms that regulate adult neurogenesis is essential to understanding how the brain may respond to neuro-inflammatory events. P2X7 receptors can regulate pro-inflammatory responses, and in addition to their role as cation channels they can trigger cell death and mediate phagocytosis. How P2X7 receptors may regulate adult neurogenesis is currently unclear. Here, neural progenitor cells (NPCs) derived from adult murine hippocampal subgranular (SGZ) and cerebral subventricular (SVZ) zones were utilized to characterize the roles of P2X7 in adult neurogenesis, and assess the effects of high extracellular ATP, characteristic of inflammation, on NPCs. Immunocytochemistry found NPCs in vivo and in vitro expressed P2X7, and the activity of P2X7 in culture was demonstrated using calcium influx and pore formation assays. Live cell and confocal microscopy, in conjunction with flow cytometry, revealed P2X7 NPCs were able to phagocytose fluorescent beads, and this was inhibited by ATP, indicative of P2X7 involvement. Furthermore, P2X7 receptors were activated with ATP or BzATP, and 5-ethynyl-2'-deoxyuridine (EdU) used to observe a dose-dependent decrease in NPC proliferation. A role for P2X7 in decreased NPC proliferation was confirmed using chemical inhibition and NPCs from P2X7 mice. Together, these data present three distinct roles for P2X7 during adult neurogenesis, depending on extracellular ATP concentrations: (a) P2X7 receptors can form transmembrane pores leading to cell death, (b) P2X7 receptors can regulate rates of proliferation, likely via calcium signaling, and (c) P2X7 can function as scavenger receptors in the absence of ATP, allowing NPCs to phagocytose apoptotic NPCs during neurogenesis. Stem Cells 2018;36:1764-1777.

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Section: Discussionmentioning

confidence: 91%

P2X7 Receptors Regulate Phagocytosis and Proliferation in Adult Hippocampal and SVZ Neural Progenitor Cells: Implications for Inflammation in Neurogenesis

et al. 2018

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“…Tat enhances the expression of monocyte chemoattractant protein 1 (MCP-1) in human astrocytes in a P2X7-dependent manner (Tewari et al, 2015 ). In addition, the glycoprotein gp120 (gp120)—an HIV envelope glycoprotein—increases P2X7 receptor expression in BV2 microglia cells (Chen et al, 2016 ) and in hippocampus of rats (Liu et al, 2017 ). Pretreatment with BBG has prevented NF-κB activation and production of inflammatory mediators induced by gp120 in BV2 cells (Chen et al, 2016 ), suggesting a key role for P2X7 receptor in HIV-induced glial cells activation and brain damage.…”

Section: P2x7 Receptor In Infectious Diseases—angel or Demon Dependinmentioning

confidence: 99%

The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

et al. 2018

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Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors—P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels). Among the P2 receptors, the P2X7 receptor is the most extensively studied from an immunological perspective, being involved in both innate and adaptive immune responses. P2X7 receptor activation induces large-scale ATP release via its intrinsic ability to form a membrane pore or in association with pannexin hemichannels, boosting purinergic signaling. ATP acting via P2X7 receptor is the second signal to the inflammasome activation, inducing both maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18, and the production of reactive nitrogen and oxygen species. Furthermore, the P2X7 receptor is involved in caspases activation, as well as in apoptosis induction. During adaptive immune response, P2X7 receptor modulates the balance between the generation of T helper type 17 (Th17) and T regulatory (Treg) lymphocytes. Therefore, this receptor is involved in several inflammatory pathological conditions. In infectious diseases and cancer, P2X7 receptor can have different and contrasting effects, being an angel or a demon depending on its level of activation, cell studied, type of pathogen, and severity of infection. In neuroinflammatory and neurodegenerative diseases, P2X7 upregulation and function appears to contribute to disease progression. In this review, we deeply discuss P2X7 receptor dual function and its pharmacological modulation in the context of different pathologies, and we also highlight the P2X7 receptor as a potential target to treat inflammatory related diseases.

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“…Psychological stress is sensed by the innate immune system in the brain via the ATP/P2RX7 pathway 21 . Aberrant P2RX7 expression in neural cells dysregulates neuronal-glial homeostasis and cognition, which may trigger the emergence of depressive symptoms 14,[22][23][24][25][26] .…”

Section: Discussionmentioning

confidence: 99%

Stress-associated purinergic receptors code for fatal suicidality in the hippocampal-hypothalamic-prefrontal circuit

Zhang

Verwer

Heerikhuize

et al. 2022

Preprint

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Imbalanced purine metabolism is a key neurological basis for suicide and mood disorders (MD), wherein purinergic receptors in stress-sensitive cerebral regions are thought to be differentially activated. A hippocampal network that links the hypothalamus and prefrontal cortex implements an affective sensation of stress. We discovered that the hippocampus encoded fatal suicidal ideations in the dentate gyrus (DG) by a considerable amount of the granule cell nuclei with P2X purinoceptor 7 (P2RX7) expression, irrespective of the underlying MD. Compared to controls, patients with MD showed microglial dyshomeostasis throughout the hippocampal formation. Strikingly, P2Y purinoceptor 12 (P2RY12)-expressing microglia with segmented processes were remarkably present in the superficial layers of the medial entorhinal cortex (mEnt) in individuals with fatal suicidality. In the hypothalamic stress-sensitive nuclei, P2RY12+ microglia were more expressed in the supraoptic nucleus in MD and even higher when fatal suicidality was present. In the prefrontal cortex, P2RX7 transcripts sharply dropped in suicidal individuals, possibly removing the prefrontal inhibition of the hippocampus and hypothalamus. Confounder analysis showed that the suicide-specific molecular features faded when the postmortem delay was prolonged. Our findings imply that fatal suicidality presents with unique neuropathological alterations. The DG and mEnt are two crucial areas for deciphering the suicidal consequences. By including brain samples from legal euthanasia donors, suicide-specific biosignatures can be maximally retained. Decoding the bioactive framework through key genes, brain regions and neurological processes involved in suicide neuropathology may provide novel therapeutic strategies for suicidal individuals who are beyond the reach of mental health care.

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P2X<sub>7</sub> receptor in the hippocampus is involved in gp120-induced cognitive dysfunction

Cited by 10 publications

References 36 publications

P2X7 Receptors Regulate Phagocytosis and Proliferation in Adult Hippocampal and SVZ Neural Progenitor Cells: Implications for Inflammation in Neurogenesis

P2X7 Receptors Regulate Phagocytosis and Proliferation in Adult Hippocampal and SVZ Neural Progenitor Cells: Implications for Inflammation in Neurogenesis

The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

Stress-associated purinergic receptors code for fatal suicidality in the hippocampal-hypothalamic-prefrontal circuit

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