title: NR2B-dependent cyclophilin D translocation suppresses the recovery of synaptic transmission after oxygen-glucose deprivation.
abstract: N-methyl d-aspartate receptor (NMDA) subunit 2B (NR2B)-containing NMDA receptors and mitochondrial protein cyclophilin D (CypD) are well characterized in mediating neuronal death after ischemia, respectively. However, whether and how NR2B and CypD work together in mediating synaptic injury after ischemia remains elusive. Using an ex vivo ischemia model of oxygen-glucose deprivation (OGD) in hippocampal slices, we identified a NR2B-dependent mechanism for CypD translocation onto the mitochondrial inner membrane. CypD depletion (CypD null mice) prevented OGD-induced impairment in synaptic transmission recovery. Overexpression of neuronal CypD mice (CypD+) exacerbated OGD-induced loss of synaptic transmission. Inhibition of CypD-dependent mitochondrial permeability transition pore (mPTP) opening by cyclosporine A (CSA) attenuated ischemia-induced synaptic perturbation in CypD+ and non-transgenic (non-Tg) mice. The treatment of antioxidant EUK134 to suppress mitochondrial oxidative stress rescued CypD-mediated synaptic dysfunction following OGD in CypD+ slices. Furthermore, OGD provoked the interaction of CypD with P53, which was enhanced in slices overexpressing CypD but was diminished in CypD-null slices. Inhibition of p53 using a specific inhibitor of p53 (pifithrin-μ) attenuated the CypD/p53 interaction following OGD, along with a restored synaptic transmission in both non-Tg and CypD+ hippocampal slices. Our results indicate that OGD-induced CypD translocation potentiates CypD/P53 interaction in a NR2B dependent manner, promoting oxidative stress and loss of synaptic transmission. We also evaluate a new ex vivo chronic OGD-induced ischemia model for studying the effect of oxidative stress on synaptic damage.
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, University of Kansas, Lawrence, KS 66045.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, University of Kansas, Lawrence, KS 66045.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, University of Kansas, Lawrence, KS 66045.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, University of Kansas, Lawrence, KS 66045.
authors.forename: Fang
authors.initials: F
authors.lastname: Du
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, University of Kansas, Lawrence, KS 66045.
authors.forename: Shirley Shidu
authors.initials: SS
authors.lastname: Yan
keywords: CypD; Mitochondria; NR2B; OGD; Synaptic transmission; p53