, 1995). The phenotype is not only linked to developmental problems, as epilepsy can also be induced in the adult mouse if a GluA2 allele lacking the ECS but silenced via a large floxed insert within

intron 11 becomes expression-activated by Cre-mediated recombination in all principal forebrain neurons ( Krestel et al., 2004). Moreover, distinct neurological dysfunctions, ranging from lethargy to hyperexcitability, are generated in mice expressing different BTK inhibition levels of Q/R site-unedited GluA2 ( Feldmeyer et al., 1999). The circuit alterations in the forebrain causing epilepsy may be related to elevated Ca2+ influx through receptors containing unedited GluA2 subunits. The severity of the phenotype is surprising, given that lack of the ECS causes transcripts to undergo attenuated intron 11 splicing, resulting in normally edited mRNAs from the wild-type allele outnumbering unedited ones from the mutant allele by at least three to one (Brusa et al., 1995). Hence, a postulated increase in Ca2+ influx through an unedited AMPA channel population CP-690550 datasheet should be modest at best, and indeed, no cell death could be observed in the brains of such mice. A plausible mechanistic link between the introduced mutation in a single Gria2 allele and the resulting mouse phenotype may be the greater tetramerization and trafficking potential of Q/R site-unedited GluA2

subunits ( Greger et al., 2002 and Greger et al., 2003). The specific impact of Q/R site editing on protein function is reminiscent of edits in the tetramerization domain of Kv channels of cephalopods (see below). Intriguingly, a potential role for Q/R site-underedited GluA2 in causing cell death has been postulated for motoneurons, based on a postmortem analysis of individuals with sporadic amyotrophic lateral sclerosis (Kawahara et al., 2004). A more recent study (Hideyama et al., 2012), also on deceased ALS patients, DNA ligase traced this underediting to downregulation of ADAR2 (but not ADAR1 and 3) in all motoneurons. Indeed, an ALS-like phenotype could be induced in mice carrying floxed ADAR2 alleles by selective Cre-mediated ADAR2 knockout in motoneurons, and no such phenotype developed

when the mice expressed pre-edited Gria2 alleles ( Hideyama et al., 2010). Thus, Q/R site underediting of GluA2 appears to induce in motoneurons a profound pathological change with relevance to ALS. As anticipated from the importance of AMPA editing, global (different from cell population selective) knockout of ADAR2, the enzyme responsible for Q/R site editing of GluA2 transcripts, results in early postnatal death of the mice. This fate can be prevented by making the mice homozygous for Gria2 alleles that carry a codon for arginine instead of glutamine for the Q/R site. The normal life span and unimpaired home cage phenotype of ADAR2-lacking mice that carry only the “pre-edited Gria2 alleles” was unexpected: ADAR2, which is widely expressed beyond the brain, is known to edit many messages besides GluA2.