Activity‐dependent intracellular chloride accumulation and diffusion controls GABA_A receptor‐mediated synaptic transmission

Abstract

In the CNS, prolonged activation of GABA(A) receptors (GABA(A)Rs) has been shown to evoke biphasic postsynaptic responses, consisting of an initial hyperpolarization followed by a depolarization. A potential mechanism underlying the depolarization is an acute chloride (Cl(-)) accumulation resulting in a shift of the GABA(A) reversal potential (E(GABA)). The amount of GABA-evoked Cl(-) accumulation and accompanying depolarization depends on presynaptic and postsynaptic properties of GABAergic transmission, as well as on cellular morphology and regulation of Cl(-) intracellular concentration ([Cl(-)](i)). To analyze the influence of these factors on the Cl(-) and voltage behavior, we studied spatiotemporal dynamics of activity-dependent [Cl(-)](i) changes in multicompartmental models of hippocampal cells based on realistic morphological data. Simulated Cl(-) influx through GABA(A) Rs was able to exceed physiological Cl(-) extrusion rates thereby evoking HCO(3)(-) -dependent E(GABA) shift and depolarizing responses. Depolarizations were observed in spite of GABA(A) receptor desensitization. The amplitude of the depolarization was frequency-dependent and determined by intracellular Cl(-) accumulation. Changes in the dendritic diameter and in the speed of GABA clearance in the synaptic cleft were significant sources of depolarization variability. In morphologically reconstructed granule cells subjected to an intense GABAergic background activity, dendritic inhibition was more affected by accumulation of intracellular Cl(-) than somatic inhibition. Interestingly, E(GABA) changes induced by activation of a single dendritic synapse propagated beyond the site of Cl(-) influx and affected neighboring synapses. The simulations suggest that E(GABA) may differ even along a single dendrite supporting the idea that it is necessary to assign E(GABA) to a given GABAergic input and not to a given neuron.

Neuronal Chloride Regulation via KCC2 Is Modulated through a GABABReceptor Protein Complex

“…Assuming E GABAA reflects E Cl − and that extracellular chloride remains constant, a 5 mV shift would equate to an increase in intracellular chloride of ∼1.2 m m (from 5.4 to 6.6 m m , according to the Nernst equation). Changes in E GABAA over a narrow range (<5 mV) can have dramatic effects upon whether GABAergic inputs have an inhibitory or facilitating effect (Morita et al, 2006; Jedlicka et al, 2011) and E GABAA changes of the same magnitude can cause significant changes in the degree of NMDA receptor activation and action potential firing frequency (Akerman and Cline, 2006; Saraga et al, 2008), which can be further influenced by the frequency and location of GABAergic inputs (Prescott et al, 2006; Jean-Xavier et al, 2007). …”

Short-term ionic plasticity at GABAergic synapses

“…This implies that multiple dendrite-targeting GABAergic inputs originating from a single pre-synaptic cell would have a larger inhibitory effect if the synapses are distributed throughout the dendritic tree, as opposed to being clustered along a single branch. Once again, such a morphological arrangement appears to be evident in different systems (Doyon et al, 2011; Jedlicka et al, 2011). …”

“…Computational models (Qian and Sejnowski, 1990; Staley and Proctor, 1999; Doyon et al, 2011; Jedlicka et al, 2011) predict that for a given amount of synaptic GABA A R activation and its accompanying Cl − influx, smaller post-synaptic volumes will result in relatively larger increases in [Cl − ] i and hence greater depolarizing shifts in E GABA . This explains the experimental finding that depolarizing responses to GABA A R activation are more easily elicited over dendritic as opposed to somatic compartments (Figure 2 and Staley and Proctor, 1999).…”

Role of the neuronal K-Cl co-transporter KCC2 in inhibitory and excitatory neurotransmission

“…This axo-somatic gradient likely reflects the differential subcellular distribution of KCC2 and NKCC1 (Khirug et al, 2008). In addition, local, activity-dependent alteration of [Cl − ] i along a single dendrite is correlated with a transient and local shift in E GABA (Dallwig et al, 1999; Staley and Proctor, 1999; Kuner and Augustine, 2000; Isomura et al, 2003; Jedlicka et al, 2011), the dynamics of which likely depends on KCC2 function [see (Doyon et al, 2011)]. Thus, KCC2 dynamically regulates the efficacy of GABA signaling through a local control over [Cl − ] i .…”