Network Dysfunction

Prof. Dr. Dietmar Schmitz

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.

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