Environmental Enrichment Reveals Effects of Genotype on Hippocampal Spine Morphologies in the Mouse Model of Fragile X Syndrome

Julie C Lauterborn,Alex H Babayan,Christine M Gall,Matiar Jafari

doi:10.1093/cercor/bht249

Julie C Lauterborn, Alex H Babayan + Show 2 more

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https://doi.org/10.1093/cercor/bht249

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Abstract

Fragile X Syndrome (FXS) and the Fmr1 knockout (KO) mouse model of this disorder exhibit abnormal dendritic spines in neocortex, but the degree of spine disturbances in hippocampus is not clear. The present studies tested if the mutation influences dendritic branching and spine measures for CA1 pyramidal cells in Fmr1 KO and wild-type (WT) mice provided standard or enriched environment (EE) housing. Automated measures from 3D reconstructions of green fluorescent protein (GFP)-labeled cells showed that spine head volumes were ∼ 40% lower in KOs when compared with WTs in both housing conditions. With standard housing, average spine length was greater in KOs versus WTs but there was no genotype difference in dendritic branching, numbers of spines, or spine length distribution. However, with EE rearing, significant effects of genotype emerged including greater dendritic branching in WTs, greater spine density in KOs, and greater numbers of short thin spines in KOs when compared with WTs. Thus, EE rearing revealed greater effects of the Fmr1 mutation on hippocampal pyramidal cell morphology than was evident with standard housing, suggesting that environmental enrichment allows for fuller appreciation of the impact of the mutation and better representation of abnormalities likely to be present in human FXS.

Highlights

Fragile X syndrome (FXS) is the most common form of inherited mental retardation
There is evidence that rearing environment influences the effect of the Fmr1 mutation on long-term potentiation (LTP): KO mice reared in an enriched environment (EE) reportedly have normal cortical potentiation, comparable to levels seen in wild-type (WT) mice housed in standard cages (Meredith et al 2007)
And in contrast to expectations from prior analyses of neocortical neurons (Restivo et al 2005), housing in the EE had greatest effects on measures of hippocampal neurons in WT mice when compared with Fmr1 KOs and increased the differences between genotypes for several of the dendrite and spine measures

Summary

Introduction

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. It is mainly caused by an expansion of CGG repeats in the Fmr gene that encodes Fragile X Mental Retardation Protein (FMRP); the expansion leads to hypermethylation that blocks FMRP expression thereby resulting in the disorder (Penagarikano et al 2007). There is evidence that rearing environment influences the effect of the Fmr mutation on LTP: KO mice reared in an enriched environment (EE) reportedly have normal cortical potentiation, comparable to levels seen in wild-type (WT) mice housed in standard cages (Meredith et al 2007).

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