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A role for Mints in transmitter release: Mint 1 knockout mice exhibit impaired GABAergic synaptic transmission.

Mints (also called X11-like proteins) are adaptor proteins composed of divergent N-terminal sequences that bind to synaptic proteins such as CASK (Mint 1 only) and Munc18-1 (Mints 1 and 2) and conserved C-terminal PTB- and PDZ-domains that bind to widely distributed proteins such as APP, presenilins, and Ca(2+) channels (all Mints). We find that Mints 1 and 2 are similarly expressed in most neurons except for inhibitory interneurons that contain selectively high levels of Mint 1. Using knockout mice, we show that deletion of Mint 1 does not impair survival or alter the overall brain architecture, arguing against an essential developmental function of the Mint 1-CASK complex. In electrophysiological recordings in the hippocampus, we observed no changes in short- or long-term synaptic plasticity in excitatory synapses from Mint 1-deficient mice and detected no alterations in the ratio of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents. Thus the Mint 1-CASK complex is not required for AMPA- and NMDA-receptor functions or for synaptic plasticity in excitatory synapses. In inhibitory synapses, however, we uncovered an approximately 3-fold increase in presynaptic paired-pulse depression, suggesting that deletion of Mint 1 impairs the regulation of gamma-aminobutyric acid release. Our data indicate that Mints 1 and 2 perform redundant synaptic functions that become apparent in Mint 1-deficient mice in inhibitory interneurons because these neurons selectively express higher levels of Mint 1 than Mint 2.

Pubmed ID: 12547917

Authors

  • Ho A
  • Morishita W
  • Hammer RE
  • Malenka RC
  • Sudhof TC

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 4, 2003

Associated Grants

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

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Brain
  • Cadherins
  • Carrier Proteins
  • Electrophysiology
  • GABA Agents
  • Genotype
  • Glutathione Transferase
  • Immunoblotting
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Models, Genetic
  • Nerve Tissue Proteins
  • Phenotype
  • Protein Structure, Tertiary
  • Recombination, Genetic
  • Synapses
  • Time Factors
  • gamma-Aminobutyric Acid