Altered mRNA Editing and Expression of Ionotropic Glutamate Receptors after Kainic Acid Exposure in Cyclooxygenase-2 Deficient Mice

Abstract

Kainic acid (KA) binds to the AMPA/KA receptors and induces seizures that result in inflammation, oxidative damage and neuronal death. We previously showed that cyclooxygenase-2 deficient (COX-2−/−) mice are more vulnerable to KA-induced excitotoxicity. Here, we investigated whether the increased susceptibility of COX-2−/− mice to KA is associated with altered mRNA expression and editing of glutamate receptors. The expression of AMPA GluR2, GluR3 and KA GluR6 was increased in vehicle-injected COX-2−/− mice compared to wild type (WT) mice in hippocampus and cortex, whereas gene expression of NMDA receptors was decreased. KA treatment decreased the expression of AMPA, KA and NMDA receptors in the hippocampus, with a significant effect in COX-2−/− mice. Furthermore, we analyzed RNA editing levels and found that the level of GluR3 R/G editing site was selectively increased in the hippocampus and decreased in the cortex in COX-2−/− compared with WT mice. After KA, GluR4 R/G editing site, flip form, was increased in the hippocampus of COX-2−/− mice. Treatment of WT mice with the COX-2 inhibitor celecoxib for two weeks decreased the expression of AMPA/KA and NMDAR subunits after KA, as observed in COX-2−/− mice. After KA exposure, COX-2−/− mice showed increased mRNA expression of markers of inflammation and oxidative stress, such as cytokines (TNF-α, IL-1β and IL-6), inducible nitric oxide synthase (iNOS), microglia (CD11b) and astrocyte (GFAP). Thus, COX-2 gene deletion can exacerbate the inflammatory response to KA. We suggest that COX-2 plays a role in attenuating glutamate excitotoxicity by modulating RNA editing of AMPA/KA and mRNA expression of all ionotropic glutamate receptor subunits and, in turn, neuronal excitability. These changes may contribute to the increased vulnerability of COX-2−/− mice to KA. The overstimulation of glutamate receptors as a consequence of COX-2 gene deletion suggests a functional coupling between COX-2 and the glutamatergic system.

Altered Electroencephalography Spectral Profiles in Rats with Different Patterns of Experimental Brain Dysplasia

“…These markers, initially described in the context of dysplasia in samples taken from cortical tubers in tuberous sclerosis complex patients (Sosunov et al, ; Talos et al, ), share a bidirectional relationship with epilepsy. Their ablation can directly lead to seizures, but in epileptic tissue their expression is actually often enhanced, likely as a form of adaptive plasticity aimed at responding to abnormal neuronal activity (Brand‐Schieber et al, ; Caracciolo et al, ; Carlen, ; Sukigara et al, ; Ohno et al, ).…”

“…These markers, initially described in the context of dysplasia in samples taken from cortical tubers in tuberous sclerosis complex patients (Sosunov et al, 2008;Talos et al, 2008), share a bidirectional relationship with epilepsy. Their ablation can directly lead to seizures, but in epileptic tissue their expression is actually often enhanced, likely as a form of adaptive plasticity aimed at responding to abnormal neuronal activity (Brand-Schieber et al, 2004;Caracciolo et al, 2011;Carlen, 2012;Sukigara et al, 2014;Ohno et al, 2015). The relative decrease in the expression of these markers at baseline (nonepilepsy) conditions, could thus potentially result in abnormal glial function (e.g., insufficient connexin coupling) or diminished ability to respond to increased excitation.…”

Restoration of Glutamatergic Transmission by Dopamine D4 Receptors in Stressed Animals

“…Our recent study has found that the detrimental effect of repeated stress on cognition is causally linked to the ubiquitin/proteasome-mediated degradation of AMPAR and NMDAR subunits and the suppression of glutamatergic transmission in PFC (44). In addition, the alteration of RNA editing of AMPAR subunits (45,46) is potentially another mechanism underlying the effects of stress.…”

Glutamate receptor and transporter modifications in rat organotypic hippocampal slice cultures exposed to oxygen–glucose deprivation: The contribution of cyclooxygenase-2

“…COX-2 has been hypothesized to attenuate glutamate excitotoxicity and, consequently, Ca 2+ influx, by indirectly modulating transcription of the ionotropic glutamatergic AMPA/KA and NMDA receptors based on COX-2-deficient mice assays (Caracciolo et al, 2011). Our study indicates that treatment with meloxicam prevents cell mortality while promotes significant increases of the NMDA and AMPA receptor subunit transcript levels, previously reduced by the OGD injury.…”

“…The meloxicam treatment also lessened the ischemic-induced increases of the glial fibrillary acidic protein (GFAP) and CD11b (Montori et al, 2010c), two inflammatory markers that are widely used in the study of the brain impairment (Giovannoni, 2006;Hamby et al, 2007;Massaro et al, 1990). The effect of meloxicam at this molecular level could be mediated by its preferential inhibitory effect on COX-2 at doses used in vivo (Fleischmann et al, 2002) since a functional coupling between COX-2 and the glutamate excitotoxicity has been reported based on COX-2-deficient mice assays, as well as the decreased expression of AMPA/ KA and N-methyl-D-aspartate receptor (NMDAR) subunits by the treatment with celecoxib COX-2 inhibitor (Caracciolo et al, 2011).…”