Dysregulation of the SNARE-binding protein Munc18-1 impairs BDNF secretion and synaptic neurotransmission: a novel interventional target to protect the aging brain

Young Il Lee, Yun Gi Kim, Hee Jang Pyeon, Jin Chul Ahn, Sreemathi Logan, Albert Orock, Kyeung Min Joo, Andrea Lőrincz, Ferenc Deák

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Brain-derived neurotrophic factor (BDNF) has a central role in maintaining and strengthening neuronal connections and to stimulate neurogenesis in the adult brain. Decreased levels of BDNF in the aging brain are thought to usher cognitive impairment. BDNF is stored in dense core vesicles and released through exocytosis from the neurites. The exact mechanism for the regulation of BDNF secretion is not well understood. Munc18-1 (STXBP1) was found to be essential for the exocytosis of synaptic vesicles, but its involvement in BDNF secretion is not known. Interestingly, neurons lacking munc18-1 undergo severe degeneration in knock-out mice. Here, we report the effects of BDNF treatment on the presynaptic terminal using munc18-1-deficient neurons. Reduced expression of munc18-1 in heterozygous (+/−) neurons diminishes synaptic transmitter release, as tested here on individual synaptic connections with FM1-43 fluorescence imaging. Transduction of cultured neurons with BDNF markedly increased BDNF secretion in wild-type but was less effective in munc18-1 +/− cells. In turn, BDNF enhanced synaptic functions and restored the severe synaptic dysfunction induced by munc18-1 deficiency. The role of munc18-1 in the synaptic effect of BDNF is highlighted by the finding that BDNF upregulated the expression of munc18-1 in neurons, consistent with enhanced synaptic functions. Accordingly, this is the first evidence showing the functional effect of BDNF in munc18-1 deficient synapses and about the direct role of munc18-1 in the regulation of BDNF secretion. We propose a molecular model of BDNF secretion and discuss its potential as therapeutic target to prevent cognitive decline in the elderly.

Original languageEnglish (US)
Pages (from-to)109-123
Number of pages15
JournalGeroScience
Volume41
Issue number2
DOIs
StatePublished - Apr 15 2019

Keywords

  • BDNF (brain-derived neurotrophic factor) secretion
  • Brain aging and dementia
  • FM 1-43 fluorescence microscopy
  • Neurotransmission
  • Synaptic vesicle recycling
  • munc18-1

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

Fingerprint Dive into the research topics of 'Dysregulation of the SNARE-binding protein Munc18-1 impairs BDNF secretion and synaptic neurotransmission: a novel interventional target to protect the aging brain'. Together they form a unique fingerprint.

  • Cite this