Figure 8. Enhancing glial K⁺ buffering by overexpressing a leak K⁺ channel rescues zyd seizures.

(A) A model for zyd function in seizure susceptibility is depicted. In wildtype cortex glia (left), oscillatory Ca²⁺ signaling maintains normal cortex glia-to-neuron communication and a balanced extracellular ionic environment. In zyd cortex glia (right), the basal elevation of Ca²⁺ leads to hyperactivation of CN and enhanced endocytosis with accumulation of early endosomes. This disrupts the endo-exocytosis balance of the K_2P leak channel sandman (and potentially other cortex glial membrane proteins) and impaired glial K⁺ buffering. (B) Behavioral analysis of the recovery from vortex-induced seizures. Pan-glial over expression of SAND:GFP partially rescues zyd seizures (~15%), while cortex-glial overexpression of a genetically modified constitutively-open Shaker K⁺ channel (termed EKO) rescues ~75% of zyd seizures. (N = 3 groups of 20 flies/genotype). (C) Behavioral analysis of HS induced seizures. Cortex glial overexpression of EKO lead to a dramatic change in the behavior of ~60% of zyd animals, showing partial recovery from the seizure phenotype to bottom dwelling and hypoactivity. (D-E) CPG recordings revealed that zyd;NP2222>EKO larvae regain rhythmic muscle activity. (D) Representative voltage traces of spontaneous CPG activity at 3^rd instar larval muscle 6 at 38°C in wildtype, zyd and zyd;NP2222>EKO (n ≥ 3 preparations/genotype). Cortex-glial expression of EKO eliminates the continuous CPG seizures observed in zyd mutants. (E) Quantification of average bursting duration for CPG recordings of the indicated genotypes at 38°C. Error bars are SEM, ****=P < 0.0001, Student’s t-test.