Journal
JOURNAL OF NEUROSCIENCE
Volume 26, Issue 50, Pages 13089-13101Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2855-06.2006
Keywords
Mint; X11; knock-out; neurotransmitter release; survival; adaptor proteins
Categories
Funding
- NIA NIH HHS [F32 AG005844, F32-AG05844] Funding Source: Medline
- NIMH NIH HHS [R37 MH052804, R37-MH52804-06] Funding Source: Medline
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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 similar to 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 similar to 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.
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