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The Journal of Neuroscience, December 13, 2006, 26(50):13089-13101; doi:10.1523/JNEUROSCI.2855-06.2006

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Cellular/Molecular
Genetic Analysis of Mint/X11 Proteins: Essential Presynaptic Functions of a Neuronal Adaptor Protein Family

Angela Ho,¹ Wade Morishita,⁵ Deniz Atasoy,¹ Xinran Liu,¹ Katsuhiko Tabuchi,¹ Robert E. Hammer,^3,4 Robert C. Malenka,⁵ and Thomas C. Südhof^1,2,4

¹Center for Basic Neuroscience, ²Departments of Molecular Genetics and ³Biochemistry, and ⁴Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, and ⁵Department of Psychiatry and Behavioral Sciences, Nancy Friend Pritzker Laboratory, Stanford University School of Medicine, Stanford, California 94304

Correspondence should be addressed to either Angela Ho or Thomas C. Südhof, the Center for Basic Neuroscience, Utah Southwestern Medical Center, 6000 Harry Hines Boulevard, NA4.118, Dallas, TX 75390-9111, Email: angela.ho{at}utsouthwestern.edu or Email: thomas.sudhof{at}utsouthwestern.edu

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.

Key words: Mint; X11; knock-out; neurotransmitter release; survival; adaptor proteins

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Received July 5, 2006; revised Nov. 8, 2006; accepted Nov. 9, 2006.

Correspondence should be addressed to either Angela Ho or Thomas C. Südhof, the Center for Basic Neuroscience, Utah Southwestern Medical Center, 6000 Harry Hines Boulevard, NA4.118, Dallas, TX 75390-9111, Email: angela.ho{at}utsouthwestern.edu or Email: thomas.sudhof{at}utsouthwestern.edu

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