P2X7 Receptor Signaling in Stress and Depression

Abstract

Stress exposure is considered to be the main environmental cause associated with the development of depression. Due to the limitations of currently available antidepressants, a search for new pharmacological targets for treatment of depression is required. Recent studies suggest that adenosine triphosphate (ATP)-mediated signaling through the P2X7 receptor (P2X7R) might play a prominent role in regulating depression-related pathology, such as synaptic plasticity, neuronal degeneration, as well as changes in cognitive and behavioral functions. P2X7R is an ATP-gated cation channel localized in different cell types in the central nervous system (CNS), playing a crucial role in neuron-glia signaling. P2X7R may modulate the release of several neurotransmitters, including monoamines, nitric oxide (NO) and glutamate. Moreover, P2X7R stimulation in microglia modulates the innate immune response by activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, consistent with the neuroimmune hypothesis of MDD. Importantly, blockade of P2X7R leads to antidepressant-like effects in different animal models, which corroborates the findings that the gene encoding for the P2X7R is located in a susceptibility locus of relevance to depression in humans. This review will discuss recent findings linked to the P2X7R involvement in stress and MDD neuropathophysiology, with special emphasis on neurochemical, neuroimmune, and neuroplastic mechanisms.

Keywords: P2X7 receptor; depression; neuroinflammation; stress.

Figure 1

Interaction between the components involved in the neurobiology of MDD. Vulnerability factors can lead to development of MDD due to induction of changes in the central nervous system including the neuroendocrine homeostasis, neurochemical alterations, and neuroplasticity impairment. The core response to stress is the HPA axis activation resulting in high circulating levels of glucocorticoids. This endocrine response leads to neuroimmune activation, inhibition of monoaminergic and facilitation of glutamatergic neurotransmissions. These systems interact, and the overall result is impairment of the neuroplasticity in cortical and limbic structures. Neuroplasticity alterations include decreased levels of neurotrophic factors (e.g., BDNF), dendritic atrophy, diminished neurogenesis and synaptogenesis and glial cells dysfunction. Impaired neuroplasticity further contributes to neurochemical imbalances. Green arrows indicate stimulation while red arrows represent inhibition. White arrow with green border means that a stimulating action was blocked. HPA: hypothalamic-pituitary-adrenal; BDNF: brain-derived neurotrophic factor.

Figure 2

Purinergic signaling. ATP is synthesized in terminal nerves, glial cells or astrocytes by mitochondrial oxidative phosphorylation, and released to extracellular space after physiological or pathological stimulus by vesicular exocytosis, transmembrane channels (pannexin, connexin) or cellular apoptosis. Extracellular ATP may either interact with P2 receptors or be rapidly metabolized to adenosine. P2 receptors are divided in P2X (cation ionotropic) and P2Y (metabotropic) receptors. Adenosine molecules may interact with P1 receptors (metabotropic), they can be reuptaken and converted back into ATP in cell cytoplasm or they can be metabolized by ADA into inosine. ATP: adenosine triphosphate; ATPase: adenosine triphosphatase; AK: adenylate kinase; AMPd: adenosine monophosphate deaminase; ADA: adenosine deaminase.

Figure 3

P2X7R-mediated NLPR3 inflammasome activation. (A) NLRP3 is composed by an N-terminal pyrin domain (PYD), a central nucleotide-binding-and-oligomerization (NATCH) domain, and a C-terminal leucine-rich repeats (LRR) domain. PYD domain recruits the apoptosis-associated speck-like protein (ASC) that contains a caspase recruitment domain (CARD). This complex recruits the procaspase-1. Together, these components constitute the NLRP3 inflammasome. (B) 1. High ATP levels released from neurons or astrocytes reach P2X7R located in microglia; 2. P2X7R stimulation elicits K⁺ efflux, which may trigger NLRP3 inflammasome assembly and activation through NIMA-related serine/threonine kinase 7 (Nek7) binding; 3. NLRP3 inflammasome mediates the activation of caspase-1; 4. Caspase-1 induces the maturation of interleukins (IL) by cleaving pro-IL-1β and pro-IL-18 in IL-1β and IL-18, respectively; 5. Finally, the mature form of cytokines are secreted.

Figure 3

P2X7R-mediated NLPR3 inflammasome activation. (A) NLRP3 is composed by an N-terminal pyrin domain (PYD), a central nucleotide-binding-and-oligomerization (NATCH) domain, and a C-terminal leucine-rich repeats (LRR) domain. PYD domain recruits the apoptosis-associated speck-like protein (ASC) that contains a caspase recruitment domain (CARD). This complex recruits the procaspase-1. Together, these components constitute the NLRP3 inflammasome. (B) 1. High ATP levels released from neurons or astrocytes reach P2X7R located in microglia; 2. P2X7R stimulation elicits K⁺ efflux, which may trigger NLRP3 inflammasome assembly and activation through NIMA-related serine/threonine kinase 7 (Nek7) binding; 3. NLRP3 inflammasome mediates the activation of caspase-1; 4. Caspase-1 induces the maturation of interleukins (IL) by cleaving pro-IL-1β and pro-IL-18 in IL-1β and IL-18, respectively; 5. Finally, the mature form of cytokines are secreted.

Figure 4

P2X7 receptor involvement in mood disorders. Stress exposure elicits a massive ATP and glutamate release with consequent activation of P2X7R and NMDA receptors, respectively. Stimulation of these receptors leads to: 1. enhanced K⁺ efflux resulting in NLRP3 inflammasome activation and secretion of inflammatory cytokines (e.g., IL-1β, IL-18, TNF-α) from astrocytes and microglia; 2. increased Ca²⁺ influx leading to ATP and glutamate release from nerve terminals and astrocytes, which is responsible to excitotoxicity; 3. NMDA-mediated nNOS activation and consequent NO formation in nerve terminals, also contributing to excitotoxicity process; 4. ROS production causing neuronal damage. Under conditions of stress, high levels of ATP, glutamate and pro-inflammatory cytokines are maintained by a regenerative circuit, even after stress stimulus termination, which leads to diminished BDNF levels, decreased synapto-/neuro-genesis and damage of brain circuits important for emotional/mood regulation. Further investigation is required to better elucidate whether P2X7R induce glutamate and ATP release by its direct action in neurons or due the indirect activation of these receptors in glial cells. ATP: adenosine triphosphate; Ca²⁺: calcium; IL-18: interleukin-18; IL-1β: interleukin-1β; K⁺: potassium; Na⁺: sodium; NMDA: N-methyl-D-aspartate receptor; nNOS: neuronal nitric oxide synthase; NO: nitric oxide, ROS: reactive oxygen species; TNF-α: tumor necrosis factor alpha.