Many studies on the mechanism of formation of the leading edge and migration focus on the cytoskeleton. Here we examined whether modulation of ion conductances is also utilized in formation of the leading edge. As formation of a leading edge is associated with volume changes and volume regulation is associated with modulation of Cl¯ conductances, we focused in our study on the impact of Cl¯ conductances on the formation of a leading edge, using the microglial cell line, BV - 2, as a model. We found that BV - 2 cells express KCl cotransporters 1 - 4 (KCC 1 - 4) by using PCR and volume regulated Cl channels by using a conventional whole cell patch clamp technique. Cl¯ conductance was completely blocked by 10 mM DIOA, a potent KCC inhibitor and 200 mM flufenamic acid, a routinely used blocker of Cl channels. Interestingly, BV - 2 cells respond to exposure to an IsoKCl solution with formation of a leading edge within a few minutes. Inhibition of Cl¯ conductances prevents leading edge formation. Increasing extracellular potassium concentration leads to an inversion of KCl transport and to a water influx. Because some studies report on a polarized distribution of ion channels, like K channels and ion transporters, like NBC1, we postulate a polarized distribution of functional KCC. Activation of this transporters involves local volume changes, thus, formation of a leading edge.