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Linking GABAergic neurones to hippocampal-entorhinal system functions

Final Report Summary - GABACELLSANDMEMORY (Linking GABAergic neurones to hippocampal-entorhinal system functions)

Many renowned labs study the properties of spatially tuned cells such as place cells in the hippocampus and of grid cells/head direction/border cells in the medial entorhinal cortex. My lab has concentrated for more than two decades on GABAergic interneurons that are hardly spatially tuned but contribute to the coordinated activity within neuronal networks. The goal of the proposed studies was to determine the functional role of GABAergic interneurons for spatial and temporal coding, for distinct oscillatory activities and spatial memory. To this end we used different mouse lines in which we modified the activity of selective GABAergic interneurons either by reducing the excitatory drive onto them or by abolishing gap junction-mediated electrical coupling. The resulting phenotypes were often unexpected and would challenge current thinking. For instance, gap junction ablation in GABAergic interneurons in the hippocampus and medial entorhinal cortex would affect the activity of the former but not latter. Such mutants are crucial for testing the interdependence of spatially tuned cells in the two major brain areas involved in spatial coding. Some mouse models were instrumental in challenging current theoretical models. For instance, recording from fast-spiking GABAergic neurons in the medial entorhinal cortex led to the refutation of much-favored theoretical models proposing how grid cell activity is generated, pointing to the need to develop models that take into consideration the new empirical data.
As often in science, during the course of the planned experiments we made unexpected findings that opened an entirely new avenue of research. Thus, based on virus-mediated tracing, we discovered a new type of GABAergic neurons, namely long-range GABAergic neurons that diverge from the classical “interneuron” phenotype, i.e. Their axon does not arborize locally but projects to remote brain areas. Using optogenetics in vitro and in vivo, we functionally characterized long-range GABAergic neurons and came to the conclusion that by virtue of their connectivity – they inhibit preferentially local interneurons in the target area - they are ideally suited to synchronize remotely located networks.
Also based on optogenetics, we characterized local and distant connectivity of defined neuronal cell types in the medial and lateral entorhinal cortex and revealed principles of connectivity that were known only in part or not at all. Of note, GABAergic interneurons mediate most of the local connectivity between excitatory cell types in the superficial layers of the medial entorhinal cortex. The data obtained in the course of this grant, with a special focus on GABAergic interneurons and projection neurons, is essential for understanding spatial coding and spatial memory.