TP3 GABAB receptor-mediated regulation of synaptic plasticity in interneurons

The goal of this project is to identify the role of GABA_B receptors (GABA_BRs) in the mediation and modulation of synaptic plasticity in GABAergic inhibitory interneurons (INs). GABA_BRs act as major regulator of plasticity in principal cells. Although there are multiple sites of action with divergent effects, as a net effect, their activation promotes Hebbian long-term potentiation (LTP) in excitatory principal cell networks. However, INs are highly diverse and their synaptic and intrinsic properties are markedly different to those of principal cells. Therefore GABA_BRs are expected to have different impact in the various IN types. Consistent with this hypothesis, in the last funding period we found that GABA_BRs show differential expression and functional effects in pre- and postsynaptic compartments of distinct IN types. We further found that GABA_BR activation inhibits, rather than facilitates, Hebbian plasticity at excitatory glutamatergic synapses onto somatostatin (SOM)-expressing INs (SOMIs) and parvalbumin (PV)-expressing INs (PVIs). In continuation of this work (1) we aim to investigate the cellular and subcellular distribution of GABA_BRs in the diverse types of cortical INs in collaboration with TP4 Kulik. (2) We will analyze the cellular and molecular mechanisms underlying the inhibitory effects of GABA_BRs on synaptic plasticity at excitatory glutamatergic synapses onto INs in close interaction with TP1 Bartos, TP2 Geiger and TP5 Wulff. (3) Investigate the involvement and relevance of GABA_BR-mediated signalling in functional and structural plasticity of GABAergic output synapses of distinct IN types in collaboration with TP1 Bartos and TP4 Kulik. (4) We will assess whether GABA_BR-mediated signalling itself can undergo long-term plasticity in INs in parallel to plastic changes at their excitatory inputs in collaboration with TP4 Kulik. Such plasticity could enhance the efficacy and dynamic range of GABA_BR effects in the control of IN recruitment. Finally, (5) we will develop microcircuit and small-scale network models to analyze the impact of these forms of plasticity for network dynamics in interaction with TP1 Bartos, TP2 Geiger and TP9 Sprekeler. To address these questions we will apply a combination of in vitro electrophysiological, neuroanatomical and computational techniques focusing on two major types of INs, perisomatic-inhibitory PV-positive basket cells (BCs), and dendritic-inhibitory SOM-expressing oriens-lacunosum-moleculare (O-LM) INs. In this project we expect to find cell type- and region specific divergence in the GABA_BR-mediated modulation of synaptic plasticity and thereby obtain a better understanding of the functional diversity of INs in terms of network state and GABAergic modulation with implications for cognitive functions, as well as disease states of the brain.