The selective antagonism of P2X(7) and P2Y(1) receptors prevents synaptic failure and affects cell proliferation induced by oxygen and glucose deprivation in rat dentate gyrus

In this work we investigated the role of P2X7 and P2Y1 receptors on the synaptic and proliferative response of the dentate gyrus (DG) to severe oxygen and glucose deprivation (OGD) in acute rat hippocampal slices. Extracellular field excitatory post-synaptic potentials (fEPSPs) in granule cells of the DG were recorded from rat hippocampal slices. Nine-min OGD elicited an irreversible loss of fEPSP and was invariably followed by the appearance of anoxic depolarization (AD). MRS2179 (selective antagonist of P2Y1 receptor) and BBG (the most used antagonist of P2X7 receptor), applied before and during OGD, prevented AD appearance and allowed a significant recovery of neurotransmission after 9-min OGD. The effects of 9-min OGD on proliferation and maturation of cells localized in the subgranular zone (SGZ) of DG of slices prepared from rats treated with 5- Bromo-2′-deoxyuridine (BrdU) were investigated. Slices were further incubated with an immature neuronal marker, doublecortin (DCX). The number of BrdU+ cells in the SGZ was significantly decreased 6 h after OGD. This effect was antagonized by BBG. Conversely, MRS2179 reduced the number of BrdU+ cells. Twenty-four hours after 9-min OGD, the number of BrdU+ cells returned to control values and an increased arborisation of tertiary dendrites of DCX+ cells was observed. This phenomenon was still evident in the presence of BBG, but not MRS2179. Results demonstrate that P2X7 and P2Y1 receptors contribute to early damage induced by OGD in the DG. Later after OGD, P2Y1 receptors might play an additional and different role promoting cell proliferation and maturation in the DG.