For example, it now appears that mutations in ADAR1 that reduce RNA editing are the root cause of Aicardi-Goutieres syndrome, a rare pediatric illness which otherwise resembles viral infection or severe systemic lupus erythematosus (SLE), and mutations in ADAR2
have been linked to a number of neurological disorders.
Ge et al., "Decrease of mRNA editing after spinal cord injury is caused by down-regulation of ADAR2
that is triggered by inflammatory response," Scientific Reports, vol.
ADAR2. The upregulation of ADAR2 by chronic treatment with fluoxetine (Table 1) depends on 5-[HT.sub.2B] receptor stimulation, since the 150-200% increase of mRNA and protein expression of ADAR2 was prevented in astrocytes treated with 5-[HT.sub.2B] receptor siRNA .
However, the effects of the gene changes of ADAR2, [cPLA.sup.2], and GluK2 are probably not further altered.
Gene Drug FACS, Culture astrocytes astrocytes ADAR2 Fluoxetine Up Up [5-HT.sub.2B] receptor expression Fluoxetine Up Up [5-HT.sub.2B] editing Fluoxetine Up Up [5-HT.sub.2C]receptor expression Fluoxetine Unchanged Unchanged [cPLA.sub.2a] Fluoxetine Up Up [sPLA.sub.2] Fluoxetine Unaltered Unaltered GluK2 expression Fluoxetine Up Up GluK2 editing Fluoxetine Up Up GluK4 expression Fluoxetine Unchanged Unchanged cfos expression Fluoxetine Up Up fosB expression Fluoxetine Up Up [Ca.sub.v ]1.2 Fluoxetine Up Up NBCel Carbamazepine Up Up GluK2 Carbamazepine Down Down [cPLA.sub.2] Carbamazepine Up Up Table 1 shows all experiments in which drug effects were compared in cultured astrocytes and in astrocytes freshly obtained by FACS as described by Lovatt et al.
Within vulnerable neurons, there is selective downregulation of ADAR2
and defective Q/R site editing of the ionotropic glutamatergic AMPA, GluR2 receptor subunit, resulting in the expression of the death-promoting calcium permeable GluR2 isoform and associated impairment in GluR2 mRNA and protein expression, receptor assembly, membrane trafficking, and synaptic targeting.