BIDIRECTIONAL ROLES OF KV2.1 IN REGULATING NEURONAL EXCITABILITY AND BURSTING

Kv2.1 is a slow delayed rectifier potassium channel encoded by the KCNB1 gene. Accounting for up to ~60% of the delayed rectifier current, Kv2.1 is widely expressed throughout the brain. However, its role in controlling neuronal excitability remains unclear. Due to their very slow kinetics, Kv2 channels impact late membrane repolarisation, thereby delaying the depolarisation block in pyramidal neurons. We confirmed this effect with patch clamp experiments on cultured hippocampal neurons and on hippocampal slices (CA1 pyramidal neurons). It is important to note that we observed high variability in responses to current injection following Kv2 current blockade using guanxitoxin-1E (GxTx). Additionally, overexpressing Kv2.1 increased neuronal excitability by enabling a higher firing frequency. This suggests that the observed variability in responses to GxTx may reflect different levels of Kv2 expression or currents. Overall, we found that GxTx can enhance or reduce excitability depending on stimulus intensity, with a subpopulation of cells displaying higher or lower susceptibility to GxTx. Notably, we also observed a bidirectional effect on bursting. Recent studies have reported that Kv2 blockade enhances bursting in both CA3 and L5 pyramidal neurons. We found that in CA1 pyramidal neurons, however, the effects of GxTx depended on the cell. In bursting neurons, GxTx stopped bursting; in non-bursting neurons, however, firing occurred in bursts after GxTx application. Together, these findings suggest that Kv2.1 acts as a bidirectional switch for neuronal excitability, depending on the previous state of neuronal excitability and stimulus intensity.