Genetic analysis of Mint/X11 proteins: Essential presynaptic functions of a neuronal adaptor protein family

Angela Ho, Wade Morishita, Deniz Atasoy, Xinran Liu, Katsuhiko Tabuchi, Robert E Hammer, Robert C. Malenka, Thomas C. Südhof

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Mints/X11s are adaptor proteins composed of three isoforms: neuron-specific Mints 1 and 2, and the ubiquitously expressed Mint 3. We have now analyzed constitutive and conditional knock-out mice for all three Mints/X11s. We found that ∼80% of mice lacking both neuron-specific Mint isoforms (Mints 1 and 2) die at birth, whereas mice lacking any other combination of Mint isoforms survive normally. The ∼20% surviving Mint 1/2 double knock-out mice exhibit a decrease in weight and deficits in motor behaviors. Hippocampal slice electrophysiology uncovered a decline in spontaneous neurotransmitter release, lowered synaptic strength, and enhanced paired-pulse facilitation in Mint-deficient mice, suggesting a decreased presynaptic release probability. Acute ablation of Mint expression in cultured neurons from conditional Mint 1/2/3 triple knock-in mice also revealed a decline in spontaneous release, confirming that deletion of Mints impair presynaptic function. Quantitation of synaptic proteins showed that acute deletion of Mints caused a selective increase in Munc18-1 and Fe65 proteins, and overexpression of Munc18-1 in wild-type neurons also produced a decrease in spontaneous release, suggesting that the interaction of Mints with Munc18-1 may contribute to the presynaptic phenotype observed in Mint-deficient mice. Our studies thus indicate that Mints are important regulators of presynaptic neurotransmitter release that are essential for mouse survival.

Original languageEnglish (US)
Pages (from-to)13089-13101
Number of pages13
JournalJournal of Neuroscience
Volume26
Issue number50
DOIs
StatePublished - Dec 13 2006

Keywords

  • Adaptor proteins
  • Knock-out
  • Mint
  • Neurotransmitter release
  • Survival
  • X11

ASJC Scopus subject areas

  • Neuroscience(all)

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