| First Author | Puntman DC | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 28 | Pages | 5980-5993 |
| PubMed ID | 34103363 | Mgi Jnum | J:354005 |
| Mgi Id | MGI:6723719 | Doi | 10.1523/JNEUROSCI.3150-20.2021 |
| Citation | Puntman DC, et al. (2021) Munc18-1 is essential for neuropeptide secretion in neurons. J Neurosci |
| abstractText | Neuropeptide secretion from dense-core vesicles (DCVs) controls many brain functions. Several components of the DCV exocytosis machinery have recently been identified, but the participation of a SEC1/MUNC18 (SM) protein has remained elusive. Here, we tested the ability of the three exocytic SM proteins expressed in the mammalian brain, MUNC18-1/2/3, to support neuropeptide secretion. We quantified DCV exocytosis at a single vesicle resolution upon action potential train-stimulation in mouse CNS neurons (of unknown sex) using pHluorin- and/or mCherry-tagged Neuropeptide-Y (NPY) or Brain-Derived Neurotrophic Factor (BDNF). Conditional inactivation of Munc18-1 abolished all DCV exocytosis. Expression of MUNC18-1, but not MUNC18-2 or MUNC18-3, supported DCV exocytosis in Munc18-1 null neurons. Heterozygous (HZ) inactivation of Munc18-1, as a model for reduced MUNC18-1 expression, impaired DCV exocytosis, especially during the initial phase of train-stimulation, when the release was maximal. These data show that neurons critically and selectively depend on MUNC18-1 for neuropeptide secretion. Impaired neuropeptide secretion may explain aspects of the behavioral and neurodevelopmental phenotypes that were observed in Munc18-1 HZ mice.SIGNIFICANCE STATEMENT:Neuropeptide secretion from dense-core vesicles (DCVs) modulates synaptic transmission, sleep, appetite, cognition and mood. However, the mechanisms of DCV exocytosis are poorly characterized. Here, we identify MUNC18-1 as an essential component for neuropeptide secretion from DCVs. Paralogs MUNC18-2 or -3 cannot compensate for MUNC18-1. MUNC18-1 is the first protein identified to be essential for both neuropeptide secretion and synaptic transmission. In heterozygous Munc18-1 neurons, that have a 50% reduced MUNC18-1 expression and model the human STXBP1 syndrome, DCV exocytosis is impaired, especially during the initial phase of train-stimulation, when the release is maximal. These data show that MUNC18-1 is essential for neuropeptide secretion and that impaired neuropeptide secretion upon reduced MUNC18-1 expression may contribute to the symptoms of STXBP1 syndrome. |
