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

Abstract 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 SummaryInformation 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.