Deregulation of the A-to-I RNA editing mechanism in psychiatric disorders.

Schizophrenia and bipolar disorder (BPD) are common neurodevelopmental disorders, characterized by various life-crippling symptoms and high suicide rates. Multiple studies support a strong genetic involvement in the etiology of these disorders, although patterns of inheritance are variable and complex. Adenosine-to-inosine RNA editing is a cellular mechanism, which has been implicated in mental disorders and suicide. To examine the involvement of altered RNA editing in these disorders, we: (i) quantified the mRNA levels of the adenosine deaminase acting on RNA (ADAR) editing enzymes by real-time quantitative polymerase chain reaction, and (ii) measured the editing levels in transcripts of several neuroreceptors using 454 high-throughput sequencing, in dorsolateral-prefrontal cortices of schizophrenics, BPD patients and controls. Increased expression of specific ADAR2 variants with diminished catalytic activity was observed in schizophrenia. Our results also indicate that the I/V editing site in the glutamate receptor, ionotropic kainate 2 (GRIK2) transcript is under-edited in BPD (type I) patients (45.8 versus 53.9%, P= 0.023). GRIK2 has been implicated in mood disorders, and editing of its I/V site can modulate Ca(+2) permeability of the channel, consistent with numerous observations of elevated intracellular Ca(+2) levels in BPD patients. Our findings may therefore, at least partly, explain a molecular mechanism underlying the disorder. In addition, an intriguing correlation was found between editing events on separate exons of GRIK2. Finally, multiple novel editing sites were detected near previously known sites, albeit most with very low editing rates. This supports the hypothesis raised previously regarding the existence of wide-spread low-level 'background' editing as a mechanism that enhances adaptation and evolvability.

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