GIRK channels play an essential role in maintaining the excitability of neurons. For example, in Trisomy 21 individuals, whose cells contain an additional copy of KCNJ6, neuronal activity was shown to be reduced due to excessive channel activity [60–62]. On the other hand, loss of GIRK2 activity in knockout mice increases susceptibility to induced seizures [20, 21]. We detected the presence of GIRK channel function in glutamatergic iNs using the ML297 agonist of GIRK1/2 heterotetramers, showing that activation led to a reduction in the frequency of action potentials induced by depolarization (Fig. 2D). However, only 6.7% of neurons responded to ML297, but overexpression of GIRK2 increased the proportion of responding neurons to 30% (Fig. 2D). We therefore chose to focus on evaluating neuronal excitability as an indirect response to changes in GIRK function.
