Spatial and Temporal Dynamics in the Ionic Driving Force for GABA_A Receptors

Figure 1

[Cl⁻]_i and the associated driving force for GABA_ARs can be subject to spatial and activity-dependent temporal variations. The upper left panel shows an example of spatially regulated [Cl⁻]_i. It has been reported that low levels of KCC2 expression within the axon initial segment enable NKCC1 to maintain relatively high levels of [Cl⁻]_i compared to the soma (indicated by the red colour inside the cell) [22–24]. This can generate a depolarising Cl⁻ driving force for GABA_ARs within the axon [21–23]. The lower left panel shows an example of short-term [Cl⁻]_i loading within dendritic branches. Cl⁻ influx associated with low-level GABA_AR activity is dealt with by Cl⁻ regulation mechanisms (left-hand dendritic branch). However, during periods of intense GABA_AR activation, if 𝐸_Cl⁻ is hyperpolarised with respect to the membrane potential, high levels of Cl⁻ influx via GABA_ARs can lead to localised increases in [Cl⁻]_i and consequently depolarising shifts in 𝐸_GABA (right-hand dendritic branch) [25, 26]. The upper right panel illustrates an example of long-term [Cl⁻]_i changes. Certain patterns of neural activity within mature neurons (e.g., repetitive coincidental pre- and postsynaptic spiking or prolonged postsynaptic spiking, interictal-like activity) can lead to a downregulation in KCC2 activity, resulting in long-term increases in [Cl⁻]_i [10, 27, 28].