PMID- 37035256
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230523
IS  - 1663-3563 (Print)
IS  - 1663-3563 (Electronic)
IS  - 1663-3563 (Linking)
VI  - 15
DP  - 2023
TI  - The effect of single-cell knockout of Fragile X Messenger Ribonucleoprotein on 
      synaptic structural plasticity.
PG  - 1135479
LID - 10.3389/fnsyn.2023.1135479 [doi]
LID - 1135479
AB  - Fragile X Syndrome (FXS) is the best-known form of inherited intellectual 
      disability caused by the loss-of-function mutation in a single gene. The FMR1 
      gene mutation abolishes the expression of Fragile X Messenger Ribonucleoprotein 
      (FMRP), which regulates the expression of many synaptic proteins. Cortical 
      pyramidal neurons in postmortem FXS patient brains show abnormally high density 
      and immature morphology of dendritic spines; this phenotype is replicated in the 
      Fmr1 knockout (KO) mouse. While FMRP is well-positioned in the dendrite to 
      regulate synaptic plasticity, intriguing in vitro and in vivo data show that wild 
      type neurons embedded in a network of Fmr1 KO neurons or glia exhibit spine 
      abnormalities just as neurons in Fmr1 global KO mice. This raises the question: 
      does FMRP regulate synaptic morphology and dynamics in a cell-autonomous manner, 
      or do the synaptic phenotypes arise from abnormal pre-synaptic inputs? To address 
      this question, we combined viral and mouse genetic approaches to delete FMRP from 
      a very sparse subset of cortical layer 5 pyramidal neurons (L5 PyrNs) either 
      during early postnatal development or in adulthood. We then followed the 
      structural dynamics of dendritic spines on these Fmr1 KO neurons by in vivo 
      two-photon microscopy. We found that, while L5 PyrNs in adult Fmr1 global KO mice 
      have abnormally high density of thin spines, single-cell Fmr1 KO in adulthood 
      does not affect spine density, morphology, or dynamics. On the contrary, neurons 
      with neonatal FMRP deletion have normal spine density but elevated spine 
      formation at 1 month of age, replicating the phenotype in Fmr1 global KO mice. 
      Interestingly, these neurons exhibit elevated thin spine density, but normal 
      total spine density, by adulthood. Together, our data reveal cell-autonomous FMRP 
      regulation of cortical synaptic dynamics during adolescence, but spine defects in 
      adulthood also implicate non-cell-autonomous factors.
CI  - Copyright (c) 2023 Gredell, Lu and Zuo.
FAU - Gredell, Marie
AU  - Gredell M
AD  - Department of Molecular, Cell and Developmental Biology, University of 
      California, Santa Cruz, Santa Cruz, CA, United States.
FAU - Lu, Ju
AU  - Lu J
AD  - Department of Molecular, Cell and Developmental Biology, University of 
      California, Santa Cruz, Santa Cruz, CA, United States.
FAU - Zuo, Yi
AU  - Zuo Y
AD  - Department of Molecular, Cell and Developmental Biology, University of 
      California, Santa Cruz, Santa Cruz, CA, United States.
LA  - eng
GR  - R01 AG071787/AG/NIA NIH HHS/United States
GR  - R01 MH109475/MH/NIMH NIH HHS/United States
GR  - R01 MH127737/MH/NIMH NIH HHS/United States
GR  - R21 HD101266/HD/NICHD NIH HHS/United States
PT  - Journal Article
DEP - 20230323
PL  - Switzerland
TA  - Front Synaptic Neurosci
JT  - Frontiers in synaptic neuroscience
JID - 101548972
PMC - PMC10076639
OTO - NOTNLM
OT  - FMRP
OT  - Fmr1
OT  - Fragile X syndrome (FXS)
OT  - cell-autonomous
OT  - dendritic spine
OT  - synaptic plasticity
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- 2023/04/11 06:00
MHDA- 2023/04/11 06:01
PMCR- 2023/01/01
CRDT- 2023/04/10 04:18
PHST- 2022/12/31 00:00 [received]
PHST- 2023/03/07 00:00 [accepted]
PHST- 2023/04/11 06:01 [medline]
PHST- 2023/04/10 04:18 [entrez]
PHST- 2023/04/11 06:00 [pubmed]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fnsyn.2023.1135479 [doi]
PST - epublish
SO  - Front Synaptic Neurosci. 2023 Mar 23;15:1135479. doi: 10.3389/fnsyn.2023.1135479. 
      eCollection 2023.