Spatial and temporal dynamics in the ionic driving force for GABA(A) receptors

Abstract

It is becoming increasingly apparent that the strength of GABAergic synaptic transmission is dynamic. One parameter that can establish differences in the actions of GABAergic synapses is the ionic driving force for the chloride-permeable GABA(A) receptor (GABA(A)R). Here we review some of the sophisticated ways in which this ionic driving force can vary within neuronal circuits. This driving force for GABA(A)Rs is subject to tight spatial control, with the distribution of Cl⁻ transporter proteins and channels generating regional variation in the strength of GABA(A)R signalling across a single neuron. GABA(A)R dynamics can result from short-term changes in their driving force, which involve the temporary accumulation or depletion of intracellular Cl⁻. In addition, activity-dependent changes in the expression and function of Cl⁻ regulating proteins can result in long-term shifts in the driving force for GABA(A)Rs. The multifaceted regulation of the ionic driving force for GABA(A)Rs has wide ranging implications for mature brain function, neural circuit development, and disease.

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) [–24]. This can generate a depolarising Cl⁻ driving force for GABA_ARs within the axon [–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].