Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior
Constanza Ahumada-Marchant,
Carlos Ancatén-Gonzalez,
Henny Haensgen,
Bastian Brauer,
Nicolas Merino-Veliz,
Rita Droste,
Felipe Arancibia,
H. Robert Horvitz,
Martha Constantine-Paton,
Gloria Arriagada,
Andrés E. Chávez,
Fernando J. Bustos
Affiliations
Constanza Ahumada-Marchant
Constantine-Paton Research Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello
Carlos Ancatén-Gonzalez
Programa de Doctorado en Ciencias, Universidad de Valparaíso
Henny Haensgen
Constantine-Paton Research Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello
Bastian Brauer
Constantine-Paton Research Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello
Nicolas Merino-Veliz
Constantine-Paton Research Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello
Rita Droste
Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, McGovern Institute for Brain Research
Felipe Arancibia
Constantine-Paton Research Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello
H. Robert Horvitz
Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, McGovern Institute for Brain Research
Martha Constantine-Paton
Department of Biology, Massachusetts Institute of Technology, McGovern Institute for Brain Research
Gloria Arriagada
Constantine-Paton Research Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello
Andrés E. Chávez
Instituto de Neurociencias, Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso
Fernando J. Bustos
Constantine-Paton Research Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello
Abstract Background The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown. Results To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments. Conclusions We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions.