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.
Ho
Angela
A
Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
Morishita
Wade
W
Hammer
Robert E
RE
Malenka
Robert C
RC
Sudhof
Thomas C
TC
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015820:Cadherins; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D004594:Electrophysiology; D018682:GABA Agents / Q000378:metabolism*; D005838:Genotype; D005982:Glutathione Transferase / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D013569:Synapses / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C513072:Apba1 protein, mouse; C491635:Apba2 protein, mouse; D015820:Cadherins; D002352:Carrier Proteins; D018682:GABA Agents; D009419:Nerve Tissue Proteins; D005680:gamma-Aminobutyric Acid; D005982:Glutathione Transferase