Figure 1.

Cross-talk between neurons, astrocytes, and microglia to induce cell death during neurodegenerative and psychiatric illnesses. ATP and glutamate (Glu) are neurotransmitters released from nerve terminals but also gliotransmitters released/secreted from astrocytes and microglia. In consequence, ATP may be released by exocytotic mechanisms from neurons/astrocytes, but also through the P2X7 receptors (P2X7Rs) themselves or pannexin-1 (Panx-1) channels from astrocytes. P2X7Rs are nonselective cationic channels and thereby entry pathways for extracellular Ca²⁺ into the cell interior and exit pathways for the loss of K⁺. Stimulation of the toll-like receptor TLR4R by lipopolysaccharide (LPS) primes the generation of the inflammatory cytokine interleukin-1β (IL-1β) by the cleavage of pro-IL-1β. This process involves nucleotide-binding, leucine-rich repeat, pyrin domain containing 3 (NLRP3) inflammasome-mediated caspase-1 activation. Impoverishment in cytoplasmic K⁺ by P2X7R activation is a major stimulus for NLRP3 activation and therefore boosts IL-1β production and secretion. Presynaptic N-methyl-D-aspartate (NMDA) receptors facilitate the release of glutamate. Reactive oxygen species (ROS) are secreted from microglial cells. ROS induces protein misfolding, glutamate is in high concentrations an excitotoxin, and the inflammatory cytokines IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) cause neuroinflammation, leading also to the release of brain-derived neurotrophic factor (BDNF). AD, Alzheimer’s disease; PD, Parkinson’s disease; HD, Huntington’s disease; SE, status epilepticus; ALS, amyotrophic lateral sclerosis; MS, multiple sclerosis. Modified with permission from Illes et al. (2019b).