Involvement of caspase-3/PTEN signaling pathway in isoflurane-induced decrease of self-renewal capacity of hippocampal neural precursor cells

Abstract

Evidence has shown that children exposed to isoflurane anesthesia in early childhood display long-term cognitive abnormalities, and decreased self-renewal capacity of hippocampal neural precursor cells (NPCs), which are associated with cognition impairment. Caspase-3 has long been considered as a mediator in isoflurane-induced neuroapoptosis. However, accumulating data indicate that caspase-3 also plays a non-apoptotic negative regulatory role in NPCs self-renewal. In this study we used in vitro NPC cultures to test whether caspase-3 and its downstream signaling effectors were involved in isoflurane-induced impairment of the self-renewal capacity of hippocampal NPCs. We showed that isoflurane exposure induced a decrease in the self-renewal capacity of hippocampal NPCs by decreasing proliferation and increasing neuronal differentiation. Furthermore, we found that isoflurane exposure significantly increased the levels of active caspase-3 and decreased the levels of phospho-PTEN under both proliferation and differentiation conditions. Inhibition of either caspase-3 with Z-DEVD-fmk or PTEN with BPV (phen) in NPCs, attenuated the isoflurane-induced decrease of their proliferation and increase of neuronal differentiation. Application of Z-DEVD-fmk also attenuated isoflurane-induced decrease in phospho-PTEN expression. Taken together, our in vitro results reveal a previously uncharacterized involvement of caspase-3/PTEN signaling in the isoflurane-induced impairment of NPCs self-renewal, and contribute to the identification of novel targets for maintaining NPCs self-renewal in isoflurane-induced cognitive dysfunction.