production of reactive oxygen species, mitochondrial dysfunction, and apoptosis in neurons in many regions of the brain, particularly in the hippocampal CA1 and CA3 subfields, and hilus of dentate gyrus. KA also produces inflammatory responses typically found in neurodegenerative diseases. Several studies suggest that KA- induced excitotoxicity can be used as a model for elucidating mechanisms underlying oxidative stress and inflammation in neurodegenerative diseases [14,16,44]. Our data show that AMPA GluR2–3 and KA GluR6 mRNA levels are up-regulated in the hippocampus of COX-22/2 mice while the mRNA expression of all NMDA receptor subunits is down-regulated. KA injection caused a general decrease in the mRNA of AMPARs (GluR1–4), KARs (GluR5, GluR7, KA1– KA2) and NMDARs (NR1, NR2a–d, NR3a) in the hippocampus of both COX-2+/+ mice and COX-22/2 mice, whereas in the cortex only KA1, NR1, NR2a and NR2c mRNA levels were decreased. These data indicate that COX-22/2 mice might suffer of an imbalance of glutamate receptor expression. We observed an increase in the transcription levels for AMPA (GluR2 and GluR3) and KA (GluR6) receptor subunits in both the hippocampus and cortex of vehicle-injected COX-22/2 mice compared to WT mice, whereas the mRNA levels of NMDA subunits were generally decreased. The net effect of this action might be an increased glutamatergic throughput of AMPARs relative to NMDA receptors. Thus, we can speculate that genetic deletion of COX- 2 alters the functional interplay between AMPA and NMDA receptors, leading to the dampening of NMDA receptors and potentiation of AMPA receptors. These data confirm a role of COX-2 in modulating the expression of glutamate receptors. Moreover, the imbalance in glutamatergic neurotransmission could contribute, at least in part, to the increased susceptibility of COX-22/2 mice to KA-induced seizure intensity and neuronal damage that we previously described [6]. The NMDA receptor is formed by NR1 subunits interacting with NR2A–D, conferring functional variability depending on the specific subunits involved [45]. NR2A and NR2B are the major NR2 subunits in the adult neocortex and hippocampus. NR2A is confined to synapses of mature neurons, whereas NR2B is distributed mainly extrasynaptically [46]. Synaptic NMDA receptor activity is extremely important for neuronal survival, while the extrasynaptic NMDAR is coupled to cell-death pathways [47]. Recently, a new mechanism of autoregulation of the NMDA receptor induced by agonists overactivaction in mature neurons has been described by Gascon and colleagues [48]. The decrease in the expression of NMDAR subunits that we found in celecoxib- treated and COX-22/2 mice after KA may be explained by this mechanism of autoregulation in response to glutamate activation. NMDAR overactivation may downregulate the function of synaptic receptors in neurons in response to excitotoxic neuronal degeneration. NR1 can also be regulated by a late-onset mechanism consisting of transcriptional suppression of NR1 obligatory subunit under excitotoxic conditions [49]. Inhibition of NR1 synthesis might also result in a progressive decrease in the activity of synaptic and extrasynaptic NMDARs. Calcium influx and brief stimulation of NMDARs with excitotoxic concentrations of agonist is sufficient to irreversibly reduce the level of this receptor subunit. These mechanisms of autoregulation of the NMDARs may also be involved in KA-induced changes in the expression of NMDARs and subsequent excitoxicity and neuronal degeneration. The increased susceptibility to KA-induced excitotoxicity of COX-22/2 mice raises an important issue regarding the possible Glutamate Receptors Editing involvement of COX-2 in neuroprotection and glutamatergic neurotransmission [6]. Specifically, COX-2 could play a role in attenuating glutamate excitotoxicity and, consequently, Ca2+ influx, by indirectly modulating the transcription of AMPA/KA and NMDA receptors. After KA injection we observed a global down-regulation of AMPA/KA and NMDA mRNA expression, in WT and to a greater extent in COX-22/2 mice. Following its depolarizing actions, KA may enhance intracellular accumulation of Ca2+ to promote selective neuronal damage. Neuronal cells might protect themselves from the damaging overstimulation, inducing the observed decrease in the overall glutamate receptors expression, in an attempt to maintain homeostasis. Our data agree with a previous report by Grooms et al (2000) showing that KA administration caused delayed death of pyramidal neurons in the hippocampal CA1 and CA3 subfields that was preceded by down-regulation of GluR2 mRNA and protein expression [50]. Thus, AMPA receptor subunits may play an important role in the neurotoxicity induced by KA, although the mechanism underlying the involvement of this class of receptors in excitotoxicity should be further investigated. It is believed that the behavioral and neuropathological changes induced by KA are initiated by the activation of KA receptors in the CA3 region of the hippocampus [10], followed by release of the endogenous excitatory amino acids, glutamate, and aspartate [11], with an activation of all types of glutamate receptors. Ohno et al (1997) [51] showed that KA-induced excitotoxicity in embryonic rat hippocampal cultures is mediated by AMPA but not KA receptors, and involves NMDA receptor-mediated toxicity through the response of KA mediated by AMPA-preferring receptors. Non-NMDA receptor-mediated excitotoxicity has been proposed to contribute to neuronal loss in a broad range of pathological conditions including hypoxia, hypoglycemia, ische- mia, epilepsy, trauma [52,53], amyotrophic lateral sclerosis [54], Huntington’s disease [55], and Alzheimer’s disease [56,57]. Regulation of glutamate receptors subunits is complex and includes several intracellular steps, from transcriptional to post- translational modifications, which may have functional conse- quences on receptor subunit rearrangement and lead to functional differences in the functioning of synaptic circuits. Specifically, several reports clearly indicate that changes in editing of specific glutamate receptor subunits are accompanied by corresponding changes in the physiological properties of the channels [23,26,27,58]. Our data indicate that KA also modulated RNA editing, a post-transcriptional mechanism known to alter func- tional properties of selected subunits of AMPA and KA receptors and to induce a fine-tuning modulation of glutamate neurotrans- mission [23]. RNA editing reaction influences the structure and, most importantly, the function of the receptor, by acting at different levels: RNA editing modulates RNA splicing of several glutamate receptors [24], and Q/R RNA editing modulates receptor transport from the endoplasmic reticulum to the plasma membrane and mediates GluR subunit tetramerization [28,29]. At the functional level, Q/R RNA editing modulates ionic transport through GluR receptor channels [26,27], whereas R/G RNA editing modulates desensitization and the recovery time of GluR receptors [30]. Thus, the physiological action of glutamate seems to rely greatly on a proper RNA editing reaction. Supporting this notion, recent reports show that changes in the editing level may have a profound impact on glutamatergic neurotransmission in epilepsy [59,60,61], amyotrophic lateral sclerosis (ALS) [62,63], spinal cord injury [43] and malignant gliomas [64]. In our study, the GluR2 Q/R site, the most important editing site for modulation of AMPA receptor channel properties, PLoS ONE | www.plosone.org 17 May 2011 | Volume 6 | Issue 5 | e19398