Regulation of synapse development, function and plasticity by the extracellular matrix of the central nervous system

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Chemical synapses represent key structures for the communication between neurons of the nervous system. These units consist of a pre- and a post-synapse, mediate the rapid and efficient signal transmission between neurons, and are surrounded by glial cells. The latter affect synaptic strength and plasticity whereby astrocytes and neurons form the so-called tripartite synapse. Astrocytes release nutrients, neurotrophins, cytokines, neurotransmitters and glycoproteins and chondroitinsulfate proteoglycans (CSPGs) of the extracellular matrix (ECM). In a project funded within the SPP-1109 Neuroglia and Synapse the laboratory has explored functions of the neural ECM for synapse formation. To this end, a culture system for primary embryonic hippocampal neurons has been developed that allows for the analysis of synapse formation in vitro. Using this system, we have been able to demonstrate that CSPGs regulate synapse density on neuronal surfaces and influence the amplitude of miniature excitatory postsynaptic currents (mEPSCs) of hippocampal neurons. The analysis of a quadruple knockout mouse mutant that misses the CSPGs neurocan and brevican as well as the glycoproteins tenascin-C and tenascin-R revealed that the neural ECM regulates synapse density within the first two weeks of culture and is required for synapse stabilization and the formation of ECM superstructures designated as perineuronal nets (PNNs) in medium term. Quadruple knockout neurons displayed a deficit of synaptic transmission that manifested in reduced mIPSCS and mEPSC frequencies. Based on these results the laboratory has developed three hypotheses that direct the aims of the present proposal. The first hypothesis assumes that the ECM environment regulates the expression of genes that are relevant for synapse formation and function. Current transcriptome analyses are in agreement with this suggestion and shall be pursued at distinct developmental stages. The second hypothesis posits that PNN structures are modified in the quadruppel knockout tissue. This assumption could be confirmed by immunocytochemistry and will be elaborated further using high resolution standard emission depletion (STED) microscopy. The third hypothesis proposes that the genetic changes of the quadruple mutant neurons and PNNs modify the activity patterns of neuronal networks. Using the multi electrode array (MEA) technology the network activities of wild type and mutant neurons shall be compared and be carried to the level of investigations of hippocampal functions in vivo. Recent genetic and neuropathological investigations have suggested an association of ECM genes with neuropsychiatric diseases. The model of the quadruple knockout mouse offers a unique opportunity to investigate the biological effects of the ECM and PNN structures in the context of synaptic functions within neuronal networks and to develop concepts relating to the significance of ECM-changes in the realm of psychiatric diseases.