PARP-1 activation causes neuronal death in the hippocampal CA1 region by increasing the expression of Ca(2+)-permeable AMPA receptors

• Published in: Neurobiology of disease 2014-10, Vol.70, p.43-52
• Main Authors: Gerace, E, Masi, A, Resta, F, Felici, R, Landucci, E, Mello, T, Pellegrini-Giampietro, D E, Mannaioni, G, Moroni, F
• Format: Article
• Language: English
• Subjects: Animals; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - pathology; CA1 Region, Hippocampal - physiopathology; CA3 Region, Hippocampal - drug effects; CA3 Region, Hippocampal - pathology; CA3 Region, Hippocampal - physiopathology; Calcium - metabolism; Caspases - metabolism; Cell Death - drug effects; Cell Death - physiology; Glucose - deficiency; Hypoxia - chemically induced; Hypoxia - drug therapy; Hypoxia - pathology; Hypoxia - physiopathology; Nerve Degeneration - chemically induced; Nerve Degeneration - drug therapy; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - metabolism; Pyramidal Cells - drug effects; Pyramidal Cells - pathology; Pyramidal Cells - physiology; Rats, Wistar; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Tissue Culture Techniques; TRPM Cation Channels - metabolism
• ISSN: 1095-953X
• DOI: 10.1016/j.nbd.2014.05.023

An excessive activation of poly(ADP-ribose) polymerases (PARPs) may trigger a form of neuronal death similar to that occurring in neurodegenerative disorders. To investigate this process, we exposed organotypic hippocampal slices to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG, 100μM for 5min), an alkylating agent widely used to activate PARP-1. MNNG induced a pattern of degeneration of the CA1 pyramidal cells morphologically similar to that observed after a brief period of oxygen and glucose deprivation (OGD). MNNG exposure was also associated with a dramatic increase in PARP-activity and a robust decrease in NAD(+) and ATP content. These effects were prevented by PARP-1 but not PARP-2 inhibitors. In our experimental conditions, cell death was not mediated by AIF translocation (parthanatos) or caspase-dependent apoptotic processes. Furthermore, we found that PARP activation was followed by a significant deterioration of neuronal membrane properties. Using electrophysiological recordings we firstly investigated the suggested ability of ADP-ribose to open TRPM2 channels in MNNG-induced cells death, but the results we obtained showed that TRPM2 channels are not involved. We then studied the involvement of glutamate receptor-ion channel complex and we found that NBQX, a selective AMPA receptor antagonist, was able to effectively prevent CA1 neuronal loss while MK801, a NMDA antagonist, was not active. Moreover, we observed that MNNG treatment increased the ratio of GluA1/GluA2 AMPAR subunit expression, which was associated with an inward rectification of the IV relationship of AMPA sEPSCs in the CA1 but not in the CA3 subfield. Accordingly, 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca(2+)-permeable GluA2-lacking AMPA receptors, reduced MNNG-induced CA1 pyramidal cell death. In conclusion, our results show that activation of the nuclear enzyme PARP-1 may change the expression of membrane proteins and Ca(2+) permeability of AMPA channels, thus affecting the function and survival of CA1 pyramidal cells.