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e.fuchs@urz.uni-heidelberg.de

About 10 – 20% of all neurons in the brain release the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). The common notion is that these neurons connect and thereby inhibit only neurons in their local network. However, exceptions to this rule were found, the best-known example being the reciprocal long-range GABAergic connectivity between the medial septum and the hippocampus. In subproject B1, we used optogenetic tools to identify and characterize long-range GABAergic projections connecting functionally interacting brain regions. These brain regions are indispensable for the formation of episodic memories and spatial navigation (hippocampus, entorhinal cortex, medial septum; Melzer et al. 2012; Fuchs et al. 2016) or motor coordination (motor cortex, striatum; Melzer et al., under revision). The generation of genetically modified mouse models allowed us to express channelrhodopsin and fluorescently-labeled proteins in subpopulations of GABAergic neurons. This method allowed us to stimulate only the long-range inhibitory axons and identify and characterize the target neurons. Of note, most of the target neurons were also inhibitory neurons; and the inhibitory connectivity between two analyzed brain areas was often reciprocal.
The identification of fluorescently labeled GABAergic long-range axons prompted us to readjust the main object of the subproject B1 (instead of analyzing the effect of interneuron-specific NMDAR knockouts on hippocampal network dynamics). Based on our results, we propose that long-range GABAergic neurons play a critical role in the temporal coordination of neuronal activity in functionally interacting brain areas. Optogenetic perturbations can be used to analyze the effects of long-range inhibition in vivo. Therefore, our data provide the groundwork to test these assumptions in the behaving animal.

Distinct corticostriatal GABAergic neurons modulate striatal output neurons and motor activity (2017) Melzer S, Gil M, Michael M, Huang KW, Monyer H Neuron, under revision .

Fuchs EC, Neitz A, Pinna R, Melzer S, Caputi A, Monyer H (2016) Local and Distant Input Controlling Excitation in Layer II of the Medial Entorhinal Cortex Neuron 89: 194-208 .

Watanabe Y, Khodosevich K, Monyer H (2014) Dendrite development regulated by the schizophrenia-associated gene FEZ1 involves the Ubiquitin protease system Cell Reports 7: 1-13 .

Melzer S, Michael M, Caputi A, Eliava M, Fuchs EC, Whittington MA, Monyer H (2012) Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex Science 335: 1506-1510 .