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

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 approximately 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 approximately 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.

Pubmed ID: 17167098

Authors

  • Ho A
  • Morishita W
  • Atasoy D
  • Liu X
  • Tabuchi K
  • Hammer RE
  • Malenka RC
  • S├╝dhof TC

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

December 13, 2006

Associated Grants

  • Agency: NIA NIH HHS, Id: F32-AG05844
  • Agency: NIMH NIH HHS, Id: R37-MH52804-06

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Cells, Cultured
  • Hippocampus
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Nerve Tissue Proteins
  • Neurons
  • Neurotransmitter Agents
  • Nuclear Proteins
  • Presynaptic Terminals
  • Protein Isoforms
  • Proteins
  • Synaptic Transmission