Developmental characteristics of dendritic spines in the dentate gyrus of Fmr1 knockout mice

Abstract

Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The neuroanatomical phenotype of adult FXS patients, as well as adult Fmr1 knockout (KO) mice, includes elevated dendritic spine density and a spine morphology profile in neocortex that resembles younger individuals. Developmental studies in mouse neocortex have revealed a dynamic phenotype that varies with age, especially during the period of synaptic pruning. Here we investigated the hippocampal dentate gyrus to determine if the FXS spine phenotype is similarly tied to periods of maturation and pruning in this brain region. We used high-voltage electron microscopy to characterize Golgi-stained spines along granule cell dendrites in Fmr1 KO and wildtype (WT) mouse dentate gyrus at postnatal days 15, 21, 30, and 60. In contrast to neocortex, dendritic spine density was higher in Fmr1 KO mice across development. Interestingly, neither genotype showed specific phases of synaptogenesis or pruning, potentially explaining the phenotypic differences from neocortex. Similarly, although the KO mice showed a more immature morphological phenotype overall than WT (higher proportion of thin headed spines, lower proportion of mushroom and stubby spines), both genotypes showed gradual development, rather than impairments during specific phases of maturation. Finally, spine length showed a complex developmental pattern that differs from other brain regions examined, suggesting dynamic regulation by FMRP and other brain region-specific proteins. These findings shed new light on FMRP’s role in development and highlight the need for new techniques to further understand the mechanisms by which FMRP affects synaptic maturation.

A deconvolution method to improve automated 3D-analysis of dendritic spines: application to a mouse model of Huntington’s disease

“…Manual counting by estimation without measurements has often been used, leading to experimentator-dependant bias. It should also be noted that the canonical mushroom/thin classification cannot necessarily be extended to all neuronal types (Grossman et al 2010). On the other hand, objective parameters for quantitative spine analysis that do not take into account this classification have already been successfully used (Vecellio et al 2000;Wallace and Bear 2004;Shen et al 2009).…”

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

“…Spine defects in cortical neurons were detected during early postnatal development (1-3 weeks) and adulthood but not in 4-week-old mice (Galvez and Greenough 2005;Nimchinsky et al 2001). However, in contrast with neocortex, spine abnormalities in the dentate gyrus remain constant during development (Grossman et al 2010). Data obtained on ex vivo and in vitro systems do not consistently corroborate in vivo observations.…”

“…Mutant mice present increase density of long, immature spines in visual cortex, somatosensory cortex, and hippocampal dentate gyrus Dolen et al 2007;Galvez and Greenough 2005;Grossman et al 2010;Irwin et al 2002;Nimchinsky et al 2001;Restivo et al 2005). Spine defects in cortical neurons were detected during early postnatal development (1-3 weeks) and adulthood but not in 4-week-old mice (Galvez and Greenough 2005;Nimchinsky et al 2001).…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…The analyzed parameters and the described dendritic spine abnormalities vary between different reports. They include in vivo and in vitro studies, as well as analyses of dendritic protrusion and filopodia density, dendritic spine classification, and dendritic arborization (see, eg, McKinney et al, 2005;de Vrij et al, 2008;Gross et al, 2010;Grossman et al, 2010). Some findings are contradictory; for example, several studies have reported significantly increased total dendritic spine density in cultured hippocampal Fmr1 KO neurons as well as in cortex and olfactorial bulb in vivo (Hayashi et al, 2007;Gross et al, 2010;Liu et al, 2011;Scotto-Lomassese et al, 2011), whereas other studies have detected increased numbers of filopodia, but no significant difference in total spine density in the cortex in vivo and in cultured hippocampal neurons (Irwin et al, 2002;de Vrij et al, 2008;Bilousova et al, 2009).…”