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.