Normal molecular specification and neurodegenerative disease-like death of spinal neurons lacking the snareassociated synaptic protein Munc18-1

Chris Law, Marcos Schaan Profes, Martin Levesque, Julia A. Kaltschmidt, Matthijs Verhage, Artur Kania

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Scopus)


The role of synaptic activity during early formation of neural circuits is a topic of some debate; genetic ablation of neurotransmitter release by deletion of the Munc18-1 gene provides an excellent model to answer the question of whether such activity is required for early circuit formation. Previous analysis of Munc18-1−/− mouse mutants documented their grossly normal nervous system, but its molecular differentiation has not been assessed. Munc18-1 deletion in mice also results in widespread neurodegeneration that remains poorly characterized. In this study, we demonstrate that the early stages of spinal motor circuit formation, including motor neuron specification, axon growth and pathfinding, and mRNA expression, are unaffected in Munc18-1−/− mice, demonstrating that synaptic activity is dispensable for early nervous system development. Furthermore, we show that the neurodegeneration caused by Munc18-1 loss is cell autonomous, consistent with apparently normal expression of several neurotrophic factors and normal GDNF signaling. Consistent with cell-autonomous degeneration, we demonstrate defects in the trafficking of the synaptic proteins Syntaxin1a and PSD-95 and the TrkB and DCC receptors inMunc18-1−/− neurons; these defects do not appear to cause ER stress, suggesting other mechanisms for degeneration. Finally, we demonstrate pathological similarities to Alzheimer's disease, such as altered Tau phosphorylation, neurofibrillary tangles, and accumulation of insoluble protein plaques. Together, our results shed new light upon the neurodegeneration observed inMunc18-1−/− mice and argue that this phenomenon shares parallels with neurodegenerative diseases.

Original languageEnglish
Pages (from-to)561-576
Number of pages16
JournalJournal of neuroscience
Issue number2
Publication statusPublished - 13 Jan 2016


  • Developmental
  • Early neuronal activity
  • Motor neurons
  • Munc18-1
  • Neurodegeneration
  • Neurosecretion

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