Previous studies showed that RNA processing (editing and splicing) of GlyRs is changed in hippocampus of patients with temporal lobe epilepsy (TLE). RNA edited GlyR α3K was shown to be involved in tonic inhibition and neurodegeneration, while the RNA edited long splice variant GlyR α3L was postulated to exert a functional role at glutamatergic synapses (Eichler et al., 2008; Eichler et al., 2009). Furthermore, it was shown the potassium- chloride cotransporter 2 (KCC2) protects neurons against

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... eurodegeneration mediated by the RNA edited short GlyR α3K185L variant. These results indicated that RNA processing of GlyR α3 and regulation of intracellular chloride may be important factors of TLE. Aim of this study was to characterize splice variant-specific effects of RNA-edited GlyR α3185L by identifying mechanisms responsible for GlyR α3K185L-dependent neurodegeneration and KCC2-dependent neuroprotection and investigating the functional impact of GlyR α3L185L on glutamatergic synaptic transmission in vivo. My study revealed that GlyR α3K185L activation changes neuronal membrane properties (membrane resistance) and thereby induces neurodegeneration. Furthermore, KCC2-mediated neuroprotection was found to depend on a structural role of KCC2 rather than involving regulation of intracellular chloride. My study also revealed that the RNA splice insert of the long GlyR α3L subunit interacts with Sec8, a component of the exocyst complex of vesicular trafficking factors, and leads to axonal expression and presynaptic localization of GlyR α3L185L. The presynaptic mode of action of this RNA-edited GlyR α3L variant facilitates synaptic transmission in vivo, and depending on the neuron type in which it was expressed, quite different phenotypes of the corresponding knockin animals were observed. Enhanced glutamatergic synaptic transmission resulted in impaired working and reference memories and cognitive dysfunction, whereas anxiety-related behavior resulted from GlyR α3L185L expression in presynaptic terminals of parvalbumin-po [...]