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B1 - Effects of interneuron-specific NMDA receptor knockout on HC network dynamics

Principal investigator(s):

Abt. Klinische Neurobiologie des Universitätsklinikums und des DKFZ
DKFZ / A230
Im Neuenheimer Feld 280
69120 Heidelberg

Tel.:
0049-6221-42-3100 / 42-3101
Fax:
0049-6221-42-3111
Internet:
www.dkfz.de/de/klinische-neurobiologie/index.php
Email:
h.monyer@dkfz-heidelberg.de

Im Neuenheimer Feld 280
69120 Heidelberg

Tel.:
06221-42-3103
Fax:
Internet:
Email:
e.fuchs@urz.uni-heidelberg.de

Projects within the BCCN:


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.

Participating groups:


Key publications:

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 .