Oxidative stress-induced mitochondrial fragmentation inhibits CREB-mediated PV regulation and facilitates caspase-3-mediated PV neuronal degeneration following status epilepticus.

Parvalbumin (PV)- expressing neurons (PV neurons) are a subpopulation of γ-aminobutyric acid (GABA)-ergic interneurons that are highly vulnerable to oxidative stress. Although mitochondrial homeostasis is an essential housekeeping function for maintaining PV expression level, the underlying mechanisms of PV downregulation caused by aberrant mitochondrial dynamics are largely unknown. In this study, using an in vivo male rat model, we found that oxidative stress induced by L-buthionine sulfoximine (BSO) reduced PV expression and cAMP-response-element-binding protein (CREB) serine (S) 133 phosphorylation through cyclin-dependent kinase 5 (CDK5)-dynamin-related protein 1 (DRP1)-mediated mitochondrial fission within hippocampal PV neurons under normal control conditions. These effects were ameliorated by roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission). Similar to BSO, WY14643-induced mitochondrial fission decreased PV expression and CREB S133 phosphorylation in PV neurons. Furthermore, CREB knockdown also led to PV downregulation without altering CDK5 activity or mitochondrial dynamics. Notably, these treatments did not lead to PV neuronal degeneration. In a pilocarpine-induced status epilepticus (SE) model, however, massive PV neuronal degeneration was observed accompanied by decreased CREB S133 phosphorylation and excessive mitochondrial fragmentation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 attenuated SE-induced PV neuronal degeneration by preserving CREB S133 phosphorylation and mitochondrial integrity. These findings indicate that the CDK5-DRP1-CREB pathway may evoke PV downregulation under sublethal oxidative stress and lead to irreversible PV neuronal degeneration under severe pathological conditions such as SE. Therefore, our findings suggest that this signaling pathway may be a therapeutic target to preserve PV neurons in neurological and psychiatric diseases.