Nuclear Factor-kappaB Is Involved In The Ketamine-induced Phenotype Loss Of Parvalbumin-interneurons

Objective:The inhibitory interneurons, which express parvalbumin (PV) play important roles in learning, memory, and signal transmission in the cerebral cortex. The dysfunction of PV-interneurons has been demonstrated to be associated with certain cognitive dysfunction such as schizophrenia, Alzheimer disease, and autism. Interneuronal oxidative status due to increased reactive oxygen species (ROS) content, which produced by interneuronal reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase subunit Nox2 can directly lead to the phenotype loss of PV interneurons. Otherwise, interneuronal oxidative status is highly associated with nuclear factor-KappaB (NF-κB) signaling pathway. So, this study is to observe whether NF-κB is involved in the regulation of decreased PV expression of PV interneurons. PV-interneurons are highly sensitive to N-methyl-D-aspartate (NMDA) receptor antagonists. NMDA receptor antagonist ketamine is often used as a tool drug to induce the phenotype loss of PV-interneurons.Methods:Part 1:Ketamine 0.5μmol/L was applied to primary neuronal cultures at development in vitro (DIV) 21 d for 0,2,6,12,24 h, respectively. Then, ROS production and parvalbumin expression of PV-containing interneurons, neuronal NF-κB activation were detected. Part 2:Ketamine 0.5μmol/L (ketamine group), ketamine 0.5μmol/L and NF-κB activation inhibitor SN50 5μmol/L (ketamine+SN50 group), ketamine 0.5μmol/L and NF-κB activation inhibitor Bay 11-7082 2μmol/L (ketamine+Bay group), or neuronal culture media (control group) alone was applied to primary neuronal cultures at development in vitro (DIV) 21 d. Ketamine 0.5μmol/L and SN50 inactive control peptide SN50M 5μmol/L (ketamine+SN50M group), ketamine 0.5μmol/L and equal volume media of Bay11-7082 dimethyl sulfoxide (DMSO) (ketamine+DMSO group), SN50, SN50M, Bay11-782, or DMSO alone as negative controls. ROS production and parvalbumin expression of PV-containing interneurons, neuronal NF-κB activation were detected.Results:Ketamine exposure at a dose of 0.5μmol/L for 24 h significantly increased ROS production (P<0.05), decreased PV expression (P<0.05) of PV-containing interneurons, as well as increased neuronal NF-κB activation (P< 0.05). Coadministration with SN50 or Bay 11-7082, ketamine has no effect on ROS production, PV expression, and neuronal NF-κB activation.Conclusions:In primary neuron cultures, NF-κB activation is involved in ketamine-induced decreased PV expression in PV-containing interneurons.