Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder
Noa Lipstein, … , Judith J. Jans, Nils Brose
Noa Lipstein, … , Judith J. Jans, Nils Brose
Published February 13, 2017
Citation Information: J Clin Invest. 2017;127(3):1005-1018. https://doi.org/10.1172/JCI90259.
View: Text | PDF
Research Article Neuroscience Article has an altmetric score of 58

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

Abstract

Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies.

Authors

Noa Lipstein, Nanda M. Verhoeven-Duif, Francesco E. Michelassi, Nathaniel Calloway, Peter M. van Hasselt, Katarzyna Pienkowska, Gijs van Haaften, Mieke M. van Haelst, Ron van Empelen, Inge Cuppen, Heleen C. van Teeseling, Annemieke M.V. Evelein, Jacob A. Vorstman, Sven Thoms, Olaf Jahn, Karen J. Duran, Glen R. Monroe, Timothy A. Ryan, Holger Taschenberger, Jeremy S. Dittman, Jeong-Seop Rhee, Gepke Visser, Judith J. Jans, Nils Brose

×

Figure 3

Munc13-1P827L increases vesicular release probability.

Options: View larger image (or click on image) Download as PowerPoint
Munc13-1P827L increases vesicular release probability. (A and B) Example...
(A and B) Example traces recorded in autaptic hippocampal (A) and striatal neurons (B) from Munc13-1 Munc13-2 DKO neurons expressing Munc13-1WT (black) or Munc13-1P827L (red/blue) during the application of 500 mM sucrose, representing the release of the RRP of SVs. (C) Plot depicting the average RRP sizes (in nC) of all neurons recorded. Individual values per neuron are indicated as circles (left: hippocampal neurons; black, Munc13-1WT; red, Munc13-1P827L) or squares (right: striatal neurons; black, Munc13-1WT; blue, Munc13-1P827L), P > 0.05; Mann-Whitney test. (D) Plot depicting the average release probability (pvr) calculated for each neuron by division of the EPSC charge by the RRP charge. Individual values per neuron are indicated as circles (left: hippocampal neurons; black, Munc13-1WT; red, Munc13-1P827L, P < 0.001) or squares (right: striatal neurons; black, Munc13-1WT; blue, Munc13-1P827L, P < 0.01); Mann-Whitney test. (E and F) Example traces of mEPSCs (E) and mIPSCs (F) from autaptic hippocampal Munc13-1 Munc13-2 DKO neurons expressing Munc13-1WT (black) or Munc13-1P827L (red/blue) recorded in the presence of 300 nM tetrodotoxin. (G) Plot depicting the average mEPSC and mIPSC frequencies. Individual values per neuron are indicated as circles (left: hippocampal neurons; black, Munc13-1WT; red, Munc13-1P827L, P < 0.05) or squares (right: striatal neurons; black, Munc13-1WT; blue, Munc13-1P827L, P < 0.01); Mann-Whitney test. (H) Plot depicting the average mEPSC and mIPSC amplitudes. Individual values per neuron are indicated as circles (left: hippocampal neurons; black, Munc13-1WT; red, Munc13-1P827L, P > 0.05) or squares (right: striatal neurons; black, Munc13-1WT; blue, Munc13-1P827L, P > 0.05); Mann-Whitney test. All error bars in the figure represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001; NS, P > 0.05. See Table 2 for further details.