Cooperational Division of Clinical Neurobiology
Prof. Dr. Hannah Monyer
The common theme of the lab projects regards mechanisms underlying brain plasticity. One effort is related to the differential contribution of distinct glutamate receptor subtypes to short- and long-term synaptic plasticity and the modulation of glutamate receptors by auxiliary proteins.Furthermore we investigate the functional role of GABAergic interneurons to learning and memory. 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 to manipulate GABAergic interneuron activity in order to probe cell and network function. Thus, we take recourse to genetically modified mice with reduced GABAergic interneuron recruitment or altered connectivity and study the effect for 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.Finally, we study plasticity resulting from the integration of newborn neurons into established postnatal networks. Neurogenesis projects focus on genes involved in cell generation, migration and differentiation.
We will extend our ongoing investigations in the following directions:
1) We will seek to unravel mechanisms by which newly identified auxiliary proteins modulate receptor signaling. We will determine interacting domains between auxiliary proteins and receptors. Furthermore we will establish whether the expression of auxiliary proteins can be modulated by activity.
2) Projects revolving around GABAergic interneuron function will entail more local genetic manipulation. So far, the genetic manipulation affected GABAergic interneurons in the whole forebrain but it would be ideal to manipulate interneurons selectively in the hippocampal-entorhinal cortex formation. Furthermore, virus-mediated gene expression of light-activated channels (e.g. Channelrhodopsin) allows 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 to establish causal relationships between GABAergic interneuron activity, spatial coding and memory. Finally, we discovered novel bidirectional GABAergic pathways between hippocampus and medial entorhinal cortex whose function for neuronal synchronization between these two major brain areas remains to be established.
3) Projects regarding neurogenesis will focus on modification of neurogenesis by environmental factors and establish the functional significance of neurogenesis for hippocampal and olfactory learning.
von Engelhardt, J., Mack, V., Sprengel, R., Kavenstock, N., Li, K.W., Stern-Bach, Y., Smit, A.B., Seeburg, P.H., Monyer, H. (2010). CKAMP44: A brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus. Science, 327, 1518-1522
Korotkova, T., Fuchs, E.C., Ponomarenko, A., von Engelhardt, J., Monyer, H. (2010). NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron, 68, 557-569
Allen, K., Fuchs, E.C., Jaschonek, H., Bannerman, D.M., Monyer, H. (2011). Gap junctions between interneurons are required for normal spatial coding in the hippocampus and short-term spatial memory. J. Neurosci., 31, 6542-6552
Inta, D.I., Alfonso, J., von Engelhardt, J., Kreuzberg, MM., Meyer, A.H., van Hooft, J.A., Monyer, H. (2008). Neurogenesis and widespread forebrain migration of distinct GABAergic neurons from the postnatal subventricular zone. Proc. Natl.Acad. Sci. U.S.A., 105, 20994-20999