A role of ADAR2 and RNA editing of glutamate receptors in mood disorders and schizophrenia.
BACKGROUND
Pre-mRNAs of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propanoic acid (AMPA)/kainate glutamate receptors undergo post-transcriptional modification known as RNA editing that is mediated by adenosine deaminase acting on RNA type 2 (ADAR2). This modification alters the amino acid sequence and function of the receptor. Glutamatergic signaling has been suggested to have a role in mood disorders and schizophrenia, but it is unknown whether altered RNA editing of AMPA/kainate receptors has pathophysiological significance in these mental disorders. In this study, we found that ADAR2 expression tended to be decreased in the postmortem brains of patients with schizophrenia and bipolar disorder.


RESULTS
Decreased ADAR2 expression was significantly correlated with decreased editing of the R/G sites of AMPA receptors. In heterozygous Adar2 knockout mice (Adar2+/- mice), editing of the R/G sites of AMPA receptors was decreased. Adar2+/- mice showed a tendency of increased activity in the open-field test and a tendency of resistance to immobility in the forced swimming test. They also showed enhanced amphetamine-induced hyperactivity. There was no significant difference in amphetamine-induced hyperactivity between Adar2+/- and wild type mice after the treatment with an AMPA/kainate receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline.


CONCLUSIONS
These findings collectively suggest that altered RNA editing efficiency of AMPA receptors due to down-regulation of ADAR2 has a possible role in the pathophysiology of mental disorders.
Mie
M
Kubota-Sakashita
Kazuya
K
Iwamoto
Miki
M
Bundo
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan. kato@brain.riken.jp.
Tadafumi
T
Kato
D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019964:Mood Disorders / Q000201:enzymology* / Q000235:genetics*; D009043:Motor Activity / Q000187:drug effects; D011180:Postmortem Changes; D011810:Quinoxalines / Q000494:pharmacology; D017393:RNA Editing / Q000187:drug effects / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000201:enzymology / Q000235:genetics*
D011810:Quinoxalines; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase