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A4 - Interactions of psychiatrically relevant molecules in synaptic transmission

Principal investigator(s):

Interdisciplinary Centre for Neurosciences
Bernstein Centre for Computational Neurosciences
Dept. Neurobiology
University of Heidelberg
Im Neuenheimer Feld 345
69120 Heidelberg


Projects within the BCCN:

Primary goal of this project is the experimental and theoretical analysis of psychiatrically relevant molecules, such as the risk gene for Schizophrenia and Autism Spectrum Disorders (ASD), the S/T-kinase AKT, in synaptic transmission. This combined experimental and theoretical approach became necessary because several aspects of our newly identified roles of AKT in synaptic transmission (Ge et al., 2017), such as the detailed presynaptic calcium dynamics or the assembly process of the vesicle release machinery, were experimentally not accessible. Since suitable theoretical models for this project were not available we first needed to establish a realistic 3D model of glutamatergic synapses that corresponds to our experimental system, the synaptic boutons of neuromuscular junctions of larvae of Drosophila melanogaster. Based on the previously developed simulation-platform UG4 that allows solving complex PDE-systems (Vogel et al., 2013) we were able to establish and functionally verify a highly realistic model that for the first time showed how the morphology and physiology of two classes of glutamatergic synapses are tuned to optimally support the typical firing rates of each of these two synapse classes (Knodel et al., 2014). This model gave the foundation for implementing highly detailed presynaptic calcium dynamics. This extension was required to be able to integrate the novel synaptic functions of the kinase AKT into the model. The latter suggest that the evolutionarily conserved kinase AKT controls the functional status of presynaptic vesicle release machineries and that malfunction of AKT results in a massive increase in spontaneous synaptic release and hence system noise (Ge et al., 2017), a potential key element in the etiology of schizophrenia or ASD.

Participating groups:

Key publications:

Ge L, Leung YY, Parisotto D, Schuster CM (2017) AKT activity controls the functional status of vesicle release machineries Under revision .
Knodel MM, Geiger R, Ge L, Bucher D, Grillo A, Wittum G, Schuster CM, Queisser G (2014) Synaptic bouton properties are tuned to best fit the prevailing firing pattern. Front Comput Neurosci 8:101 .
(2013) UG4: a novel flexible software system for simulating PDE based models on high-performance computers. Comp.Vis.Sci. 16(4), 165-169 .