PMID- 37323585
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230619
IS  - 1662-5102 (Print)
IS  - 1662-5102 (Electronic)
IS  - 1662-5102 (Linking)
VI  - 17
DP  - 2023
TI  - Investigating cell-specific effects of FMRP deficiency on spiny projection 
      neurons in a mouse model of Fragile X syndrome.
PG  - 1146647
LID - 10.3389/fncel.2023.1146647 [doi]
LID - 1146647
AB  - INTRODUCTION: Fragile X syndrome (FXS), resulting from a mutation in the Fmr1 
      gene, is the most common monogenic cause of autism and inherited intellectual 
      disability. Fmr1 encodes the Fragile X Messenger Ribonucleoprotein (FMRP), and 
      its absence leads to cognitive, emotional, and social deficits compatible with 
      the nucleus accumbens (NAc) dysfunction. This structure is pivotal in social 
      behavior control, consisting mainly of spiny projection neurons (SPNs), 
      distinguished by dopamine D1 or D2 receptor expression, connectivity, and 
      associated behavioral functions. This study aims to examine how FMRP absence 
      differentially affects SPN cellular properties, which is crucial for categorizing 
      FXS cellular endophenotypes. METHODS: We utilized a novel Fmr1-/y::Drd1a-tdTomato 
      mouse model, which allows in-situ identification of SPN subtypes in FXS mice. 
      Using RNA-sequencing, RNAScope and ex-vivo patch-clamp in adult male mice NAc, we 
      comprehensively compared the intrinsic passive and active properties of SPN 
      subtypes. RESULTS: Fmr1 transcripts and their gene product, FMRP, were found in 
      both SPNs subtypes, indicating potential cell-specific functions for Fmr1. The 
      study found that the distinguishing membrane properties and action potential 
      kinetics typically separating D1- from D2-SPNs in wild-type mice were either 
      reversed or abolished in Fmr1-/y::Drd1a-tdTomato mice. Interestingly, 
      multivariate analysis highlighted the compound effects of Fmr1 ablation by 
      disclosing how the phenotypic traits distinguishing each cell type in wild-type 
      mice were altered in FXS. DISCUSSION: Our results suggest that the absence of 
      FMRP disrupts the standard dichotomy characterizing NAc D1- and D2-SPNs, 
      resulting in a homogenous phenotype. This shift in cellular properties could 
      potentially underpin select aspects of the pathology observed in FXS. Therefore, 
      understanding the nuanced effects of FMRP absence on SPN subtypes can offer 
      valuable insights into the pathophysiology of FXS, opening avenues for potential 
      therapeutic strategies.
CI  - Copyright (c) 2023 Giua, Lassalle, Makrini-Maleville, Valjent, Chavis and Manzoni.
FAU - Giua, Gabriele
AU  - Giua G
AD  - INMED, INSERM U1249, Marseille, France.
AD  - Aix-Marseille University, Marseille, France.
AD  - Cannalab "Cannabinoids Neuroscience Research International Associated 
      Laboratory", INSERM-Aix-Marseille University/Indiana University, Marseille, 
      France.
FAU - Lassalle, Olivier
AU  - Lassalle O
AD  - INMED, INSERM U1249, Marseille, France.
AD  - Aix-Marseille University, Marseille, France.
AD  - Cannalab "Cannabinoids Neuroscience Research International Associated 
      Laboratory", INSERM-Aix-Marseille University/Indiana University, Marseille, 
      France.
FAU - Makrini-Maleville, Leila
AU  - Makrini-Maleville L
AD  - IGF, University of Montpellier, INSERM, CNRS, Montpellier, France.
FAU - Valjent, Emmanuel
AU  - Valjent E
AD  - IGF, University of Montpellier, INSERM, CNRS, Montpellier, France.
FAU - Chavis, Pascale
AU  - Chavis P
AD  - INMED, INSERM U1249, Marseille, France.
AD  - Aix-Marseille University, Marseille, France.
AD  - Cannalab "Cannabinoids Neuroscience Research International Associated 
      Laboratory", INSERM-Aix-Marseille University/Indiana University, Marseille, 
      France.
FAU - Manzoni, Olivier J J
AU  - Manzoni OJJ
AD  - INMED, INSERM U1249, Marseille, France.
AD  - Aix-Marseille University, Marseille, France.
AD  - Cannalab "Cannabinoids Neuroscience Research International Associated 
      Laboratory", INSERM-Aix-Marseille University/Indiana University, Marseille, 
      France.
LA  - eng
PT  - Journal Article
DEP - 20230530
PL  - Switzerland
TA  - Front Cell Neurosci
JT  - Frontiers in cellular neuroscience
JID - 101477935
PMC - PMC10264852
OTO - NOTNLM
OT  - D1R
OT  - D2R
OT  - Fragile X
OT  - accumbens
OT  - spiny projection neurons
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/06/16 06:42
MHDA- 2023/06/16 06:43
PMCR- 2023/01/01
CRDT- 2023/06/16 04:00
PHST- 2023/01/17 00:00 [received]
PHST- 2023/05/16 00:00 [accepted]
PHST- 2023/06/16 06:43 [medline]
PHST- 2023/06/16 06:42 [pubmed]
PHST- 2023/06/16 04:00 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fncel.2023.1146647 [doi]
PST - epublish
SO  - Front Cell Neurosci. 2023 May 30;17:1146647. doi: 10.3389/fncel.2023.1146647. 
      eCollection 2023.