Background. The hippocampus is one of the few regions in the adult mammalian brain where new neurons can be continuously generated. In previous work we have shown, that newly generated young granule cells in the adult hippocampus receive the first glutamatergic synaptic inputs well before ~3 weeks after mitosis and show enhanced synaptic plasticity. However, as synaptic currents are initially small, synaptically induced AP firing has not been shown before 4 weeks post mitosis. Recently, we could show for the first time that indeed APs can be evoked in younger cells (< 3 weeks) by coincident glutamatergic and depolarizing GABAergic synaptic inputs. GABA is believed to support functional maturation of new neurons. However, the impact of synaptically evoked AP firing for synaptic plasticity and new synapse formation in the young neurons is unknown.Specific Aims. In the new project we will test the hypothesis that depolarizing GABAergic synaptic inputs control synaptic plasticity and promote the formation of new glutamatergic synapses. We will investigate GABAergic synaptic coincidence detection and the interaction with the first glutamatergic synaptic inputs. As a model system we will use adult transgenic mice which express DsRed under the control of the DCX promoter, labelling cells up to 3 weeks post mitosis and virus-mediated birth dating. First, we will study conditional AP firing evoked by coincident GABAergic and glutamatergic synaptic inputs. We will use optogenetic stimulation of different interneurons together with stimulation of coincident EPSPs as well as paired recordings from interneurons and granule cells to uncover the interneuron subtypes and the firing activity necessary for cooperative excitation and inhibition of action potential output. Second, we will focus on induction of synaptic plasticity. Our preliminary data indicate that glutamatergic contacts onto young cells show large NMDAR-mediated and very small AMPAR-mediated EPSCs. Thus we will test the hypothesis that GABA-dependent spiking generates relief of Mg2+ block from synaptic NMDA receptors and promote the induction of NMDA-dependent LTP. On the other hand, subthreshold GABAergic depolarisation might promote the induction of LTD. Third, activation of extrasynaptic glutamate receptors by spillover from neighbouring synapses will be studied. We will test whether GABAergic depolarisation will help to relief Mg2+ block from extrasynaptic NMDA receptors activated by iontophoresis or caged glutamate and may induce plasticity of spillover responses as a first step towards new glutamatergic synapse formation.Significance. The proposed experiments will help to understand, how young neurons manage to integrate into pre-existing mature neuronal networks. This is not only important to understand the mechanisms underlying adult neurogenesis, but will also help to successfully design future strategies for neuroregeneration and treatment of hippocampal dysfunction in cognitive disorders.