PMID- 37714309
OWN - NLM
STAT- Publisher
LR  - 20231022
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 187
DP  - 2023 Oct 15
TI  - VPS13A knockdown impairs corticostriatal synaptic plasticity and locomotor 
      behavior in a new mouse model of chorea-acanthocytosis.
PG  - 106292
LID - S0969-9961(23)00307-8 [pii]
LID - 10.1016/j.nbd.2023.106292 [doi]
AB  - Chorea-acanthocytosis (ChAc) is an inherited neurodegenerative movement disorder 
      caused by VPS13A gene mutations leading to the absence of protein expression. The 
      striatum is the most affected brain region in ChAc patients. However, the study 
      of the VPS13A function in the brain has been poorly addressed. Here we generated 
      a VPS13A knockdown (KD) model and aimed to elucidate the contribution of VPS13A 
      to synaptic plasticity and neuronal communication in the corticostriatal circuit. 
      First, we infected primary cortical neurons with miR30-shRNA against VPS13A and 
      analyzed its effects on neuronal plasticity. VPS13A-KD neurons showed a higher 
      degree of branching than controls, accompanied by decreased BDNF and PSD-95 
      levels, indicative of synaptic alterations. We then injected AAV-KD bilaterally 
      in the frontal cortex and two different regions of the striatum of mice and 
      analyzed the effects of VPS13A-KD on animal behavior and synaptic plasticity. 
      VPS13A-KD mice showed modification of the locomotor behavior pattern, with 
      increased exploratory behavior and hyperlocomotion. Corticostriatal dysfunction 
      in VPS13A-KD mice was evidenced by impaired striatal long-term depression (LTD) 
      after stimulation of cortical afferents, which was partially recovered by BDNF 
      administration. VPS13A-KD did not lead to neuronal loss in the cortex or the 
      striatum but induced a decrease in the neuronal release of CX3CL1 and triggered a 
      microglial reaction, especially in the striatum. Notably, CX3CL1 administration 
      partially restored the impaired corticostriatal LTD in VPS13A-KD mice. Our 
      results unveil the involvement of VPS13A in neuronal connectivity modifying BDNF 
      and CX3CL1 release. Moreover, the involvement of VPS13A in synaptic plasticity 
      and motor behavior provides key information to further understand not only ChAc 
      pathophysiology but also other neurological disorders.
CI  - Copyright (c) 2023. Published by Elsevier Inc.
FAU - Garcia-Garcia, Esther
AU  - Garcia-Garcia E
AD  - Dept Biomedical Sciences, School of Medicine and Health Sciences, Institute of 
      Neurosciences, Universitat de Barcelona, E-08036 Barcelona, Spain; August Pi i 
      Sunyer Biomedical Research Institute (IDIBAPS), E-08036 Barcelona, Spain; 
      Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), 
      E-08036 Barcelona, Spain. Electronic address: egarcia92@ub.edu.
FAU - Ramon-Lainez, Alba
AU  - Ramon-Lainez A
AD  - Dept Biomedical Sciences, School of Medicine and Health Sciences, Institute of 
      Neurosciences, Universitat de Barcelona, E-08036 Barcelona, Spain; August Pi i 
      Sunyer Biomedical Research Institute (IDIBAPS), E-08036 Barcelona, Spain; 
      Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), 
      E-08036 Barcelona, Spain. Electronic address: ramon-lainez@ub.edu.
FAU - Conde-Berriozabal, Sara
AU  - Conde-Berriozabal S
AD  - Dept Biomedical Sciences, School of Medicine and Health Sciences, Institute of 
      Neurosciences, Universitat de Barcelona, E-08036 Barcelona, Spain; August Pi i 
      Sunyer Biomedical Research Institute (IDIBAPS), E-08036 Barcelona, Spain; 
      Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), 
      E-08036 Barcelona, Spain. Electronic address: saraconde@ub.edu.
FAU - Del Toro, Daniel
AU  - Del Toro D
AD  - Dept Biomedical Sciences, School of Medicine and Health Sciences, Institute of 
      Neurosciences, Universitat de Barcelona, E-08036 Barcelona, Spain; August Pi i 
      Sunyer Biomedical Research Institute (IDIBAPS), E-08036 Barcelona, Spain; 
      Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), 
      E-08036 Barcelona, Spain. Electronic address: danieldeltoro@ub.edu.
FAU - Escaramis, Georgia
AU  - Escaramis G
AD  - Dept Biomedical Sciences, School of Medicine and Health Sciences, Institute of 
      Neurosciences, Universitat de Barcelona, E-08036 Barcelona, Spain; Biomedical 
      Research Networking Center for Epidemiology and Public Health (CIBERESP), 
      Ministerio de Ciencia e Innovacion, Madrid, Spain. Electronic address: 
      gescaramis@ub.edu.
FAU - Giralt, Albert
AU  - Giralt A
AD  - Dept Biomedical Sciences, School of Medicine and Health Sciences, Institute of 
      Neurosciences, Universitat de Barcelona, E-08036 Barcelona, Spain; August Pi i 
      Sunyer Biomedical Research Institute (IDIBAPS), E-08036 Barcelona, Spain; 
      Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), 
      E-08036 Barcelona, Spain. Electronic address: albertgiralt@ub.edu.
FAU - Masana, Merce
AU  - Masana M
AD  - Dept Biomedical Sciences, School of Medicine and Health Sciences, Institute of 
      Neurosciences, Universitat de Barcelona, E-08036 Barcelona, Spain; August Pi i 
      Sunyer Biomedical Research Institute (IDIBAPS), E-08036 Barcelona, Spain; 
      Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), 
      E-08036 Barcelona, Spain. Electronic address: mmasana@ub.edu.
FAU - Alberch, Jordi
AU  - Alberch J
AD  - Dept Biomedical Sciences, School of Medicine and Health Sciences, Institute of 
      Neurosciences, Universitat de Barcelona, E-08036 Barcelona, Spain; August Pi i 
      Sunyer Biomedical Research Institute (IDIBAPS), E-08036 Barcelona, Spain; 
      Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), 
      E-08036 Barcelona, Spain; Production and Validation Center of Advanced Therapies 
      (Creatio), Faculty of Medicine and Health Science, University of Barcelona, 
      E-08036 Barcelona, Spain. Electronic address: alberch@ub.edu.
FAU - Rodriguez, Manuel J
AU  - Rodriguez MJ
AD  - Dept Biomedical Sciences, School of Medicine and Health Sciences, Institute of 
      Neurosciences, Universitat de Barcelona, E-08036 Barcelona, Spain; August Pi i 
      Sunyer Biomedical Research Institute (IDIBAPS), E-08036 Barcelona, Spain; 
      Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), 
      E-08036 Barcelona, Spain. Electronic address: marodriguez@ub.edu.
LA  - eng
PT  - Journal Article
DEP - 20230913
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
SB  - IM
OTO - NOTNLM
OT  - BDNF
OT  - Basal ganglia disorders
OT  - CX3CL1
OT  - Long-term depression
OT  - Neuronal plasticity
OT  - VPS13A disease
COIS- Declaration of Competing Interest The authors declare no competing interests.
EDAT- 2023/09/16 05:42
MHDA- 2023/09/16 05:42
CRDT- 2023/09/15 19:13
PHST- 2023/07/28 00:00 [received]
PHST- 2023/09/01 00:00 [revised]
PHST- 2023/09/12 00:00 [accepted]
PHST- 2023/09/16 05:42 [pubmed]
PHST- 2023/09/16 05:42 [medline]
PHST- 2023/09/15 19:13 [entrez]
AID - S0969-9961(23)00307-8 [pii]
AID - 10.1016/j.nbd.2023.106292 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2023 Oct 15;187:106292. doi: 10.1016/j.nbd.2023.106292. Epub 2023 
      Sep 13.