Clinical Neurobiology

GABAergic interneurons are the principal source of inhibition in the adult brain and synchronize the activity of neuronal networks with millisecond precision, a prerequisite for most higher brain functions. Projects focusing on GABAergic interneuron function are tightly interlinked and include studies at the molecular-cellular, network and behavioral level. We identified molecular targets that are ideal for manipulating GABAergic interneuron activity in order to probe cell and network function. Thus, we utilize genetically modified mice with reduced GABAergic interneuron recruitment or altered connectivity and study the effect on spatial coding and memory. We focus on the hippocampal-entorhinal formation, a brain structure that is required for spatial navigation in rodents and episodic memory in humans. We employ optogenetics to identify and manipulate GABAergic interneuron activity in freely moving mice. Finally, we study plasticity resulting from the integration of newborn neurons into established postnatal networks in the olfactory bulb and in the hippocampus. Neurogenesis projects focus on genes involved in cell generation, migration and differentiation.

FUTURE OUTLOOK
We will extend our ongoing investigations in the following directions:

Projects revolving around GABAergic interneuron function will entail more local genetic manipulation. So far, genetic manipulation affected GABAergic interneurons in the whole forebrain, but it would be ideal to manipulate interneurons selectively in the hippocampal-entorhinal cortex formation. To this end, we employ virus-mediated gene expression of light-activated channels (e.g. Channelrhodopsin) that allow for the reliable on-line identification of GABAergic interneurons in freely moving mice and subsequent interference with the cellular activity during behavioral performance. This approach opens up possibilities for establishing causal relationships between GABAergic interneuron activity, spatial coding and memory. Finally, we have discovered novel GABAergic pathways between hippocampus and medial entorhinal cortex as well as many other brain areas whose function for neuronal synchronization between these two major brain areas remains to be established.

Projects regarding neurogenesis will focus on modification of neurogenesis by environmental factors and will establish the functional significance of neurogenesis for hippocampal and olfactory learning.