Abstract
Organotypic hippocampal slice cultures were used to model the effects of neuroinflammatory conditions following an epileptic state on functional P2X7 receptors (Rs) of subgranular zone (SGZ) neural progenitor cells (NPCs). The compound, 4-aminopyridine (4-AP), is known to cause pathological firing of neurons, consequently facilitating the release of various transmitter substances including ATP. Lipopolysaccharide (LPS) and interleukin-1β (IL-1β) both potentiated the dibenzoyl-ATP (Bz-ATP)-induced current amplitudes in NPCs, although via different mechanisms. Whereas LPS acted via promoting ATP release, IL-1β acted via its own receptor to directly influence P2X7Rs. Thus, the effect of LPS was inhibited by the ecto-ATPase inhibitor, apyrase, but not by the IL-1β antagonist, interleukin-1RA (IL-1RA); by contrast, the effect of IL-1β was inhibited by IL-1RA, but not by apyrase. Eventually, incubation with 4-AP upregulated the number of nestin/glial fibrillary acidic protein/P2X7R immunoreactive cells and their appropriate staining intensity, suggesting increased synthesis of P2X7Rs at NPCs. In conclusion, inflammatory cytokines accumulating after epilepsy-like neuronal firing may facilitate the effect of endogenous ATP at P2X7Rs of NPCs, thereby probably promoting necrosis/apoptosis and subsequent cell death.
Highlights
In the adult mammalian brain, the subgranular zone (SGZ) of the hippocampal dentate gyrus is one of the regenerative niches where neural progenitor cells (NPCs) are produced to give rise to the three main neural cell linages, i.e., neurons, astrocytes, and oligodendrocytes [1,2,3]
There are good reasons to speculate that the massive outflow of ATP from the epileptic focus may stimulate P2X7Rs, which are linked to the NLRP3/ASC inflammasome assembly, fostering the maturation and release of inflammatory cytokines such as interleukin-1β (IL-1β), especially from microglia [16]
Combination of four criteria can verify that both potentiated the dibenzoyl-ATP (Bz-ATP) at a submaximal concentration of 300 μM selectively activates the P2X7Rs in SGZ NPCs: (1) the responses to both Bz-ATP and ATP are potentiated in a low-X2+ bath medium; (2) Bz-ATP causes comparable inward currents at about 10-times lower concentrations than ATP itself; (3) the Bz-ATP effect is nearly abolished by the highly selective P2X7R antagonist A-438079; and (4) the Bz-ATP current exhibits a reversal potential around 0 mV, characteristic for non-selective cationic channels [18]
Summary
In the adult mammalian brain, the subgranular zone (SGZ) of the hippocampal dentate gyrus is one of the regenerative niches where neural progenitor cells (NPCs) are produced to give rise to the three main neural cell linages, i.e., neurons, astrocytes, and oligodendrocytes [1,2,3]. During their integration into the hippocampal circuits, NPCs pass through various consecutive developmental stages before differentiating to newborn and subsequently mature granule cells (glutamatergic projection neurons to CA3 pyramidal neurons). It was proposed that, preceding the activation of P2X7Rs, the stimulation of lipopolysaccharide (LPS)-targeted Toll-like receptors (TLRs) leads to the accumulation of cytoplasmic pro-IL-1β, which is processed to mature IL-1β under the influence of P2X7Rs [17]
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