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

• Main Authors: Katherine M. Bland, Adam Aharon, Eden L. Widener, M. Irene Song, Zachary O. Casey, Yi Zuo, George S. Vidal
• Format: Article
• Language: English
• Published: Elsevier 2021-03-01
• Series: Neurobiology of Disease
• Subjects: Fragile X Syndrome; Fmr1; Dendritic spine; Dendrite; Layer V; Layer 5
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996121000024

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.