Alterations in CA1 hippocampal synapses in a mouse model of fragile X syndrome

Abstract

Fragile X Syndrome (FXS) is the major cause of inherited mental retardation and the leading genetic cause of Autism spectrum disorders. FXS is caused by mutations in the Fragile X Mental Retardation 1 (Fmr1) gene, which results in transcriptional silencing of Fragile X Mental Retardation Protein (FMRP). To elucidate cellular mechanisms involved in the pathogenesis of FXS, we compared dendritic spines in the hippocampal CA1 region of adult wild-type (WT) and Fmr1 knockout (Fmr1-KO) mice. Using diolistic labeling, confocal microscopy, and three-dimensional electron microscopy, we show a significant increase in the diameter of secondary dendrites, an increase in dendritic spine density, and a decrease in mature dendritic spines in adult Fmr1-KO mice. While WT and Fmr1-KO mice had the same mean density of spines, the variance in spine density was three times greater in Fmr1-KO mice. Reduced astrocyte participation in the tripartite synapse and less mature post-synaptic densities were also found in Fmr1-KO mice. We investigated whether the increase in synaptic spine density was associated with altered synaptic pruning during development. Our data are consistent with reduced microglia-mediated synaptic pruning in the CA1 region of Fmr1-KO hippocampi when compared with WT littermates at postnatal day 21, which is the peak period of synaptic pruning in the mouse hippocampus. Collectively, these results support abnormal synaptogenesis and synaptic remodeling in mice deficient in FMRP. Deficits in the maturation and distribution of synaptic spines on dendrites of CA1 hippocampal neurons may play a role in the intellectual disabilities associated with FXS.

Exercise Reverses Behavioral and Synaptic Abnormalities after Maternal Inflammation

“…The modification of dentate gyrus-hippocampal CA3 connections may affect the functional connectivity of the hippocampus with other brain regions, which is associated with autistic-like behaviors in mice (Zhan et al, 2014). In addition, the increased density of functional mossy fiber synapses in adult MIA offspring is consistent with previous studies that demonstrated increased excitability and spine density of hippocampal neurons in rodent models of ASD (Tyzio et al, 2014;Jawaid et al, 2018).…”

“…The frequency of neurodevelopmental disorders is positively correlated with maternal immune activation (MIA), which is induced by viral infection during pregnancy (Knuesel et al, 2014), and several studies have reported that deficits in synap-tic function and structure underlie the pathogenesis of neurodevelopmental disorders (Koyama and Ikegaya, 2015). Specifically, the disruption of synapse excitatory versus inhibitory (E/I) balance (Rubenstein and Merzenich, 2003;Yizhar et al, 2011;Tyzio et al, 2014) and the increased spine or synapse density (Tang et al, 2014;Jawaid et al, 2018;Andoh et al, 2016) are shared pathological features between ASD patients and ASD animal models. These findings motivated us to examine whether voluntary exercise in adulthood reverses the behavioral abnormalities and affects synaptic properties in mouse offspring prenatally subjected to MIA (MIA offspring).…”

Multifaceted Changes in Synaptic Composition and Astrocytic Involvement in a Mouse Model of Fragile X Syndrome

“…Our results are consistent with reported data in adult FMR1 knock-out mice suggesting cortical circuit changes such as increase in smaller size immature synapses and decrease in larger size synapses (as evidenced by the spine size in [35,71]), as well as decreased association of astrocytes with hippocampal synapses [35]. We have extended these observations, by showing that these changes are not uniform, but depend on the synapse type, as well as cortical layer.…”

Neuroinflammatory Gene Expression Alterations in Anterior Cingulate Cortical White and Gray Matter of Males With Autism Spectrum Disorder

“…The reduction in the mRNA of these molecules in this study would support that, at least at the gene level, alterations in the complement expression in the brain may result in synaptic hyperconnectivity as it has been shown in animals through reductions or knockout of pro-inflammatory cytokines [Chu et al, 2010;Weinhard et al, 2018]. Excessive hyperconnectivity of synapses has been shown in mouse models of syndromic ASD including fragile X, tuberous sclerosis, and 15q duplication [Jawaid et al, 2018;Sato & Okabe, 2019;Tang et al, 2014].…”