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.

Reduced Hippocampal Activation During Recall is Associated with Elevated FMR1 mRNA and Psychiatric Symptoms in Men with the Fragile X Premutation

“…Such developmental consequences could be caused either by elevated FMR1 mRNA (Tassone et al 2000a, b, c;Jacquemont et al 2003;Oostra and Willemsen 2003;Allen et al 2004;Hagerman and Hagerman 2004) or a mild reduction in FMRP as is known to occur in individuals with the premutation, especially with high CGG repeat numbers (Tassone et al 2000a,b,c;Kenneson et al 2001;Entezam et al 2007). We would expect lower FMRP to result in abnormally reduced pruning during development (Irwin et al 2000;Bagni and Greenough 2005;McKinney et al 2005;Grossman et al 2006) which would in theory result in larger and potentially more active hippocampi. It is possible that lowered FMRP and increased mRNA, which can co-occur in carriers with the premutation, are affecting hippocampal structure and function in different ways, complicating the picture and making molecular/fMRI associations difficult to clearly discern, especially in so small a sample.…”

Fragile X: Translation in Action

“…This increased ongoing protein synthesis (and turnover) may account for another phenotype that has been observed in visual cortex, the increased density (by about 20%), and length of dendritic spines (McKinney et al, 2005).…”

Advances in behavioral genetics: mouse models of autism

“…84 Synaptic dysregulation in genetic mouse models for autism Although the mouse model for FXS does not fully recapitulate the behavioral phenotype of the clinical disease, there are very interesting symmetries between findings of abnormal dendritic spine morphology, including alterations in length and density, in brain of human patients and in Fmr1-null mice. 101,102 Further work has shown that Fmrp loss has marked effects on measures of synaptic plasticity in mutant mice, with significant enhancement of mGluR (group 1 metabotropic glutamate receptor) dependent long-term depression (LTD) in hippocampus, [103][104][105] and decreased cortical long-term potentiation (LTP). 106,107 The molecular mechanisms underlying these changes have yet to be elucidated, but are thought to be related to the role of FMRP in mRNA transport and translation.…”