Dendritic spine abnormalities in the occipital cortex of C57BL/6Fmr1 knockout mice

Abstract

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. Observed neuropathologies associated with FXS include abnormal length, morphology, and density of dendritic spines, reported in individuals with FXS and in Fmr1 knockout (KO) mice, an animal model of FXS. To date, however, these neuropathologies have been studied in Fmr1 KO mice bred in a FVB background (a strain with genetic mutations that complicate interpretation of results) and findings have been inconsistent. Here, Golgi-Cox impregnation was used to investigate length, morphology, and density of dendritic spines on layer V pyramidal neurons in visual cortices of Fmr1 KO and wildtype (WT) mice bred in a C57BL/6 background. We report that spine abnormalities in these animals parallel abnormalities reported in humans with FXS, perhaps to a greater degree than KO mice bred in an FVB background. Specifically, Fmr1 KO mice bred in a C57BL/6 background exhibited significantly more longer dendritic spines and fewer shorter spines, as well as more spines with immature-appearing morphology and fewer with mature-appearing morphology than WT littermates. Spine length abnormalities were demonstrated to be largely independent of spine morphology abnormalities, as the length phenotype was observed in KOs even within a morphological category. Fmr1 KO mice also had a greater overall spine density than WTs. These findings provide powerful support for the essence of the dendritic spine abnormalities in the absence of FMRP, now found to be largely consistent with human data across two mouse backgrounds.