FMRP regulates the subcellular distribution of cortical dendritic spine density in a non-cell-autonomous manner

NEUROBIOLOGY OF DISEASE

卷:150

Article

Bland, Katherine M.¹  Aharon, Adam²  Widener, Eden L.¹  Song, M. Irene¹  Casey, Zachary O.¹  Zuo, Yi²  Vidal, George S.¹ 

[1] James Madison Univ, Dept Biol, Harrisonburg, VA 22801 USA

[2] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA

关键词: Fragile X Syndrome;    Fmr1;    Dendritic spine;    Dendrite;    Layer V;    Layer 5;    Pyramidal neuron;    Cerebral cortex;    Mosaic;    Cell-autonomous;   

DOI  :  10.1016/j.nbd.2021.105253

来源: Elsevier

【 摘 要 】

Fragile X syndrome (FXS) is the most common form of intellectual disability that arises from the dysfunction of a single gene-Fmr1. The main neuroanatomical correlate of FXS is elevated dendritic spine density on cortical pyramidal neurons, which has been modeled in Fmr1(-/Y) mice. However, the cell-autonomous contribution of Fmr1 on cortical dendritic spine density has not been assessed. Even less is known about the role of Fmr1 in heterozygous female mosaic mice, which are a putative model for human Fmr1 full mutation carriers (i.e., are heterozygous for the full Fmr1-silencing mutation). In this neuroanatomical study, spine density in cortical pyramidal neurons of Fmr1(+/-) and Fmr1(-/Y) mice was studied at multiple subcellular compartments, layers, and brain regions. Spine density in Fmr1(+/-) mice is higher than WT but lower than Fmr1(-/Y). Not all subcellular compartments in layer V Fmr1(+/-) and Fmr1(-/Y) cortical pyramidal neurons are equally affected: the apical dendrite, a key subcellular compartment, is principally affected over basal dendrites. Within apical dendrites, spine density is differentially affected across branch orders. Finally, identification of FMRP-positive and FMRP-negative neurons within Fmr1(+/-) permitted the study of the cell-autonomous effect of Fmr1 on spine density. Surprisingly, layer V cortical pyramidal spine density between FMRP-positive and FMRP-negative neurons does not differ, suggesting that the regulation of the primary neuroanatomical defect of FXS-elevated spine density-is non-cell-autonomous.