Bidirectional GABAergic control of AP firing in newly-generated young granule cells of the adult hippocampus

Abstract

Gamma-aminobutyric acid (GABA) is the first transmitter which provides synaptic input to newly generated neurons. In the first 2-3 weeks after mitosis, young neurons show an elevated intracellular chloride concentration due to the expression of the NKCC1 Cl- importer. Hence, GABAergic transmission provides depolarization to the newborn cells, which is known to be crucial for activity-dependent cell survival, development and functional maturation. However, it is still unknown whether activation of GABAergic synapses can evoke action potential (AP) firing in newly generated granule cells of the adult hippocampus to induce these trophic effects. In order to address this question, young neurons of the adult brain were fluorescently labeled using either retrovirus-based GFP expression or transgenic mice expressing the red fluorescent protein DsRed under the control of the doublecortin (DCX)-promoter. Electrophysiological recordings were performed on acute hippocampal brain slices. Gramicidin perforated-patch recordings revealed a reversal potential of GABAergic synaptic currents substantially more positive in 2-3 week old DCX-expressing neurons (~-35 mV) as compared to mature granule cells (~-75 mV). In both perforated-patch and whole-cell configuration, GABAergic synaptic currents are indeed able to excite AP firing and to modulate glutamatergic subthreshold inputs. Due to the high input resistance and the slow membrane time constant of young granule cells, low GABAergic synaptic inputs result in a long lasting depolarization, which provides the basis for an efficient temporal integration of excitatory postsynaptic potentials with an enhanced firing probability for ~200 ms. Thereby, GABAergic synaptic currents boost AP firing in young granule cells within a conductance window between ~0.5 and 3.5 nS. Larger GABAergic inputs however effectively block AP firing via shunting inhibition, which might be important to protect the young cells from over excitation. Synaptic GABAergic transmission was fully blocked by 10 µM gabazine, whereas a half maximal inhibitory concentration (0.2 µM) increased AP firing at high stimulation intensities, showing that both AP generation and shunting inhibition are mediated by GABAA receptor mediated chloride conductances. Taken together, this study shows that GABAergic synaptic inputs in newly generated young granule cells can dynamically support either AP firing or shunting inhibition dependent on hippocampal network activity.