Developmental Modulation of GABAA Receptor Function by RNA Editing

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Abstract
Adenosine-to-inosine (A-to-I) editing of RNA transcripts is an increasingly recognized cellular strategy to modulate the function of proteins involved in neuronal excitability. We have characterized the editing of transcripts encoding the α3 subunit of heteromeric GABAA receptors (Gabra3), in which a genomically encoded isoleucine codon (ATA) is converted to a methionine codon (ATI) in a region encoding the predicted third transmembrane domain of this subunit. Editing at this position (I/M site) was regulated in a spatiotemporal manner with ∼90% of the Gabra3 transcripts edited in most regions of adult mouse brain, but with lower levels of editing in the hippocampus. Editing was low in whole-mouse brain at embryonic day 15 and increased during development, reaching maximal levels by postnatal day 7. GABA-evoked current in transfected cells expressing nonedited α3(I)β3γ2L GABAA receptors activated more rapidly and deactivated much more slowly than edited α3(M)β3γ2L receptors. Furthermore, currents from nonedited α3(I)β3γ2L receptors were strongly outwardly rectifying (corresponding to chloride ion influx), whereas currents from edited α3(M)β3γ2L receptors had a more linear current/voltage relationship. These studies suggest that increased expression of the nonedited α3(I) subunit during brain development, when GABA is depolarizing, may allow the robust excitatory responses that are critical for normal synapse formation. However, the strong chloride ion influx conducted by receptors containing the nonedited α3(I) subunit could act as a shunt to prevent excessive excitation, providing the delicate balance necessary for normal neuronal development.