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Previously, we have identified the presynaptic protein Munc13\u20101 as a diacylglycerol\/phorbolester (DAG\/PE) receptor that contributes to secretory, non\u2010amyloidogenic APP processing after PE stimulation. Here, we used organotypic brain slice cultures from wild\u2010type mice and from Munc13\u20101 knock\u2010out (KO), Munc13\u20102 KO and Munc13\u20101\/2 double KO (DKO) mice for pharmacological stimulation experiments. First, we demonstrate that neuronal populations and synaptic components important for secretory APP processing develop normally in organotypic brain slice cultures of all genotypes analyzed. Blockade of voltage\u2010gated Na<jats:sup>+<\/jats:sup> channels by tetrodotoxin reduced the PE\u2010stimulated secretory APP processing, whereas depolarization by high extracellular K<jats:sup>+<\/jats:sup> concentration evoked APP secretion. Additionally, the PE\u2010stimulated APP secretion from Munc13\u20101 KO brain slices was significantly lower than that from wild\u2010type brain slices. This effect was not observed in brain slices from Munc13\u20102 KO mice, which is consistent with the lower abundance and subpopulation\u2010specific distribution of Munc13\u20102 in presynaptic elements. In Munc13\u20101\/2 DKO brain slices, the deficiency of Munc13\u20101 dominated the effect of APP processing. The Munc13\u20101 KO effect on APP processing could be rescued by the stimulation of postsynaptic glutamatergic receptors. This indicates that lack of postsynaptic glutamate receptor stimulation in Munc13\u20101 KO brain slice cultures but not presynaptic mechanisms account for compromised APP processing. We conclude that organotypic brain slices cultures are a valuable tool for studying APP processing pathways in intact neuronal circuits and that neuronal activity is important for maintenance of the non\u2010amyloidogenic APP processing.<\/jats:p>","DOI":"10.1016\/j.ijdevneu.2012.10.001","type":"journal-article","created":{"date-parts":[[2012,10,13]],"date-time":"2012-10-13T01:17:21Z","timestamp":1350091041000},"page":"36-45","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Munc13 genotype regulates secretory amyloid precursor protein processing via postsynaptic glutamate receptors"],"prefix":"10.1002","volume":"31","author":[{"given":"Maike","family":"Hartlage\u2010R\u00fcbsamen","sequence":"first","affiliation":[{"name":"Paul Flechsig Institute for Brain Research University of Leipzig 04109 Leipzig 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