Network Dysfunction
Prof. Dr. Dietmar Schmitz
Group Leader and Site Speaker
Charitéplatz 1
10117 Berlin

dietmar.schmitz@dzne.de
 +49 30 450-539054

Areas of investigation/research focus

Memory consolidation takes place not only at the cellular but also at the systemic level. In the context of systems consolidation, trace-transfer consolidation emphasizes the transfer of memory traces over time, for example from the hippocampus to the cortex. Surprisingly, analyses of disease models have mainly focused on synaptic functions, but the few available investigations have indicated that important dysfunctions exist on the systemic level. We use in vivo and in vitro techniques to study the physiology and pathophysiology of neuronal networks and aim to elucidate whether and how neuronal networks are disturbed in Alzheimer's disease by the use of mouse models that display amyloid and Tau pathology. Finally, we will study the hippocampus proper and other brain areas such as the entorhinal cortex and the piriform cortex, because the latter are affected early in Alzheimer's disease. Together, these studies will help to unravel the network mechanisms underlying neurological diseases.

The entorhinal cortex (EC) is a key brain structure relaying memory related information between the neocortex and the hippocampus. The medial EC (MEC) performs several independent neuronal computations for spatial learning and memory. Besides, in many neurodegenerative diseases the MEC is severely affected by extensive neuronal loss. Since little is known about the intrinsic microcircuitry of the MEC, it has been difficult to find cellular correlates of the network functions. To resolve these issues, the Schmitz group has explored the micro-circuitry of the MEC in wild-type and AD brains. Specifically, we examined the oscillatory activity of the MEC, especially in the gamma frequency range, as it might provide insights into the connectivity profiles of the excitatory and the inhibitory neurons within these local networks. In APP/PS1 mice, we found prominent activity in the gamma oscillatory range both in the lateral EC (LEC) as well as the MEC. However, in the transgenic mouse model used, we observe early changes (4 months) exclusively in the LEC (Klein et al., 2016). This correlates well with plaque development, where a higher proportion is seen in the LEC compared to the MEC.

In parallel, we have extended studies on inhibitory/excitatory microcircuitry in the MEC (Beed et al., 2010; Beed et al., 2013) by looking at detailed morphology and connectivity of underlying neurons/interneurons by using multiple patch recordings (Winterer et al., 2017). As a future goal, we plan to investigate the role of the different participating neurons/interneurons in the ongoing oscillatory activity in physiology and pathophysiology, leading to a greater understanding of the cellular - network level organization in the MEC.

Key Publications

A. Vanessa Stempel, Alexander Stumpf, Hai-Ying Zhang, Tuğba Özdoğan, Ulrike Pannasch, Anne-Kathrin Theis, David-Marian Otte, Alexandra Wojtalla, Ildikó Rácz, Alexey Ponomarenko, Zheng-Xiong Xi, Andreas Zimmer, Dietmar Schmitz. Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus. Neuron. 2016 May 17; 90:795-809. doi: 10.1016/j.neuron.2016.03.034
Prateep Beed, Anja Gundlfinger, Sophie Schneiderbauer, Jie Song, Claudia Böhm, Andrea Burgalossi, Michael Brecht, Imre Vida, Dietmar Schmitz. Inhibitory gradient along the dorsoventral axis in the medial entorhinal cortex. Neuron. 2013 Sep 17; 79:1197-1207. doi: 10.1016/j.neuron.2013.06.038
Karen S. Y. Liu, Matthias Siebert, Sara Mertel, Elena Knoche, Stephanie Wegener, Carolin Wichmann, Tanja Matkovic, Karzan Muhammad, Harald Depner, Christoph Mettke, Johanna Bückers, Stefan W. Hell, Martin Müller, Graeme W. Davis, Dietmar Schmitz, Stephan J. Sigrist. RIM-binding protein, a central part of the active zone, is essential for neurotransmitter release. Science. 2011 Dec 15; 334:1565-1569. doi: 10.1126/science.1212991
Trimbuch T, Beed P, Vogt J, Schuchmann S, Maier N, Kintscher M, Breustedt J, Schuelke M, Streu N, Kieselmann O, Brunk I, Laube G, Strauss U, Battefeld A, Wende H, Birchmeier C, Wiese S, Sendtner M, Kawabe H, Kishimoto-Suga M, Brose N, Baumgart J, Geist B, Aoki J, Savaskan NE, Brauer AU, Chun J, Ninnemann O, Schmitz D, Nitsch R. Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling. Cell. 2009 Sep 18; 138:1222-35. doi: 10.1016/j.cell.2009.06.050
Mellor J, Nicoll RA, Schmitz D. Mediation of hippocampal mossy fiber long-term potentiation by presynaptic Ih channels. Science. 2002 Jan 04; 295:143-7. doi: 10.1126/science.1064285

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