AUTHOR=Gredell Marie , Lu Ju , Zuo Yi 

TITLE=The effect of single-cell knockout of Fragile X Messenger Ribonucleoprotein on synaptic structural plasticity

JOURNAL=Frontiers in Synaptic Neuroscience

VOLUME=15

YEAR=2023

URL=https://www.frontiersin.org/journals/synaptic-neuroscience/articles/10.3389/fnsyn.2023.1135479

DOI=10.3389/fnsyn.2023.1135479

ISSN=1663-3563

ABSTRACT=<p>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 <italic>FMR1</italic> 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 <italic>Fmr1</italic> knockout (KO) mouse. While FMRP is well-positioned in the dendrite to regulate synaptic plasticity, intriguing <italic>in vitro</italic> and <italic>in vivo</italic> data show that wild type neurons embedded in a network of <italic>Fmr1</italic> KO neurons or glia exhibit spine abnormalities just as neurons in <italic>Fmr1</italic> 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 <italic>Fmr1</italic> KO neurons by <italic>in vivo</italic> two-photon microscopy. We found that, while L5 PyrNs in adult <italic>Fmr1</italic> global KO mice have abnormally high density of thin spines, single-cell <italic>Fmr1</italic> 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 <italic>Fmr1</italic> 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.</p>