Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

Abstract

IntroductionGlutamate is the main neurotransmitter responsible for excitatory neurotransmission throughout the brain. Glutamate serves as a ligand for G-protein coupled metabotropic and ionotropic (iGluRs) receptors. The latter consists of N-methyl-D-aspartate, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate (KA) subtypes. Glutamate dysfunction has been linked to numerous diseases, including schizophrenia, bipolar disorder and major depressive disorder. 1-6The AMPA and KA receptors are ligand-gated nonselective cation channels that mediate fast excitatory neurotransmission. Each receptor is a tetramer composed of a combination of subunits encoded by separate genes, GluA1-4 for AMPA, and GluK1-3 and KA1-2 for KA receptors. Individual subunit transcripts undergo posttranscriptional modifications that substantially alter the structure and function of the resulting receptors. Alternative splicing of GluA1-4 generates 2 different variants of each subunit (flip or flop), forming AMPA receptors with distinct kinetic properties. [7][8][9] In addition, AMPA and KA receptor transcripts can be modified by RNA editing. 10The most frequent RNA editing process in eukaryotes involves conversion of adenosine to inosine catalyzed by the adenosine deaminases acting on RNA (ADAR) enzymes.11 As inosine is interpreted as a guanosine during splicing and translation, the editing event can result in recoding. A total of Background: Dysfunction of glutamate neurotransmission has been implicated in the pathology of schizophrenia and bipolar disorder, and one mechanism by which glutamate signalling can be altered is through RNA editing of ionotropic glutamate receptors (iGluRs). The objectives of the present study were to evaluate the editing status of iGluRs in the human prefrontal cortex, determine whether iGluR editing is associated with psychiatric disease or suicide and evaluate a potential association between editing and alternative splicing in the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) iGluR subunits' pre-mRNA. Methods: We studied specimens derived from patients with antemortem diagnoses of bipolar disorder (n = 31) or schizophrenia (n = 34) who died by suicide or other causes, and from psychiatrically healthy controls (n = 34) who died from causes other than suicide. The RNA editing at all 8 editing sites within AMPA (GluA2-4 subunits) and kainate (GluK1-2 subunits) iGluRs was analyzed using a novel real-time quantitative polymerase chain reaction assay. Results: No differences in editing were detected among schizophrenia, bipolar or control groups or between suicide completers and patients who died from causes other than suicide. The editing efficiency was significantly higher in the flop than in the flip splicoforms of GluA3-4 AMPA subunits (all p < 0.001). Limitations: The study is limited by the near absence of specimens from medicationnaive psychiatric patients and considerable variation in medication regimens among individuals, both of which introduce considerable uncertainty into the ana...

A role of ADAR2 and RNA editing of glutamate receptors in mood disorders and schizophrenia

“…Lyddon and colleagues examined the RNA editing in AMPA/kainate receptors in the same samples (i.e., the Neuropathology Consortium samples) [ 17 ]. Their finding that the flop isoform of GRIA3 and GRIA4 showed higher R/G site editing compared with the flip isoform was replicated in this study.…”

“…The number of studies regarding the RNA editing of AMPA/kainate receptors is relatively small. While several studies showed no alteration in schizophrenia [ 16 , 17 ] and bipolar disorder [ 17 ], a recent study revealed altered editing of the I/V site of GRIK2 in bipolar disorder [ 6 ]. The role of RNA editing of glutamate receptors has drawn attention because the glutamatergic hypothesis of mood disorders has recently been established [ 18 ].…”

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

“…Lack of such a difference after administration of an AMPA receptor antagonist suggested that this was related to altered function of glutamate receptors. 77 Another study showed no difference in RNA editing of glutamate receptors in BD, 78 whereas reduced editing of AMPA receptors was found in schizophrenia. 79…”

Advances in the pharmacology of lGICs auxiliary subunits

“…Each gene can yield several splice variants, which may form channels with different kinetics. Additionally, GluA2 mRNAs editing allows further changes in channel properties [91].…”