Coincident glutamatergic depolarizations enhance GABAA receptor-dependent Cl- influx in mature and suppress Cl- efflux in immature neurons

The impact of GABAergic transmission on neuronal excitability depends on the Cl−-gradient across membranes. However, the Cl−-fluxes through GABAA receptors alter the intracellular Cl− concentration ([Cl−]i) and in turn attenuate GABAergic responses, a process termed ionic plasticity. Recently it has been shown that coincident glutamatergic inputs significantly affect ionic plasticity. Yet how the [Cl−]i changes depend on the properties of glutamatergic inputs and their spatiotemporal relation to GABAergic stimuli is unknown. To investigate this issue, we used compartmental biophysical models of Cl− dynamics simulating either a simple ball-and-stick topology or a reconstructed immature CA3 neuron. These computational experiments demonstrated that glutamatergic co-stimulation enhances GABA receptor-mediated Cl− influx at low and attenuates or reverses the Cl− efflux at high initial [Cl−]i. The size of glutamatergic influence on GABAergic Cl−-fluxes depends on the conductance, decay kinetics, and localization of glutamatergic inputs. Surprisingly, the glutamatergic shift in GABAergic Cl−-fluxes is invariant to latencies between GABAergic and glutamatergic inputs over a substantial interval. In agreement with experimental data, simulations in a reconstructed CA3 pyramidal neuron with physiological patterns of correlated activity revealed that coincident glutamatergic synaptic inputs contribute significantly to the activity-dependent [Cl−]i changes. Whereas the influence of spatial correlation between distributed glutamatergic and GABAergic inputs was negligible, their temporal correlation played a significant role. In summary, our results demonstrate that glutamatergic co-stimulation had a substantial impact on ionic plasticity of GABAergic responses, enhancing the destabilization of GABAergic inhibition in the mature nervous systems, but suppressing GABAergic [Cl−]i changes in the immature brain. Therefore, glutamatergic shift in GABAergic Cl−-fluxes should be considered as a relevant factor of short term plasticity. Author Summary Information processing in the brain requires that excitation and inhibition are balanced. The main inhibitory neurotransmitter in the brain is gamma-amino-butyric acid (GABA). GABA actions depend on the Cl−-gradient, but activation of ionotropic GABA receptors causes Cl−-fluxes and thus reduces GABAergic inhibition. Here, we investigated how a coincident membrane depolarization by excitatory, glutamatergic synapses influences GABA-induced Cl−-fluxes using a biophysical compartmental model of Cl− dynamics, simulating either simple or realistic neuron topologies. We demonstrate that glutamatergic co-stimulation directly affects GABA-induced Cl−-fluxes, with the size of glutamatergic effects depending on the conductance, the decay kinetics, and localization of glutamatergic inputs. We also show that the glutamatergic shift in GABAergic Cl−-fluxes is surprisingly stable over a substantial range of latencies between glutamatergic and GABAergic inputs. We conclude from these results that glutamatergic co-stimulation alters GABAergic Cl−-fluxes and in turn affects the strength of GABAergic inhibition. These coincidence-dependent ionic changes should be considered as a relevant factor of short term plasticity in the CNS.