Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile‐X knockout mice

Abstract

Fragile-X syndrome is a common form of mental retardation resulting from the inability to produce the fragile-X mental retardation protein. The specific function of this protein is unknown; however, it has been proposed to play a role in developmental synaptic plasticity. Examination of human brain autopsy material has shown that fragile-X patients exhibit abnormalities in dendritic spine structure and number, suggesting a failure of normal developmental dendritic spine maturation and pruning in this syndrome. Similar results using a knockout mouse model have previously been described; however, it was noted in retrospect that the mice used in that study may have carried a mutation for retinal degeneration, which may have affected cell morphology in the visual cortex of those animals. In this study, dendritic spines on layer V pyramidal cells of visual cortices, taken from fragile-X knockout and wild-type control mice without the retinal degeneration mutation and stained using the Golgi-Cox method, were investigated for comparison with the human condition. Quantitative analyses of the lengths, morphologies, and numbers of dendritic spines, as well as amount of dendritic arbor and dendritic branching complexity, were conducted. The fragile-X mice exhibited significantly more long dendritic spines and significantly fewer short dendritic spines than control mice. Similarly, fragile-X mice exhibited significantly more dendritic spines with an immature-like morphology and significantly fewer with a more mature type morphology. However, unlike the human condition, fragile-X mice did not exhibit statistically significant dendritic spine density differences from controls. Fragile-X mice also did not demonstrate any significant differences from controls in dendritic tree complexity or dendritic arbor. Long dendritic spines with immature morphologies are characteristic of early development or a lack of sensory experience. These results are similar to those found in the human condition and further support a role for the fragile-X mental retardation protein specifically in normal dendritic spine developmental processes. They also support the validity of these mice as a model of fragile-X syndrome.

Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses

“…These mice show immature dendritic spine morphology similar to that observed in human fragile X patients (4,31). Here, we investigate rapid neurotransmitter-induced translation in synaptoneurosomes of fmr1-KO and WT mice.…”

“…Because of the abnormal dendritic spine morphology observed in human fragile X patients and fmr1-KO mice (3,4,31,38), we next considered whether postsynaptic compartments in KO mice might reseal into smaller synaptic structures than those of WT mice, altering the probability that they contain translation components. Synaptoneurosome preparations were examined by electron microscopy for possible differences in the size or shape of the postsynaptic components.…”

Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

“…However, at the single-neuron level (using the Golgi impregnation technique on postmortem brain tissue), cortical neurons in several regions have abnormal dendrites, with spines showing excessive numbers and length [Rudelli et al, 1985;Hinton et al, 1991;Wisniewski et al, 1991;Irwin et al, 2001]. Similar studies in the Fmr1 mutant mouse confirmed these findings, as well as excessive dendritic branching [Comery et al, 1997;Irwin et al, 2002;Galvez et al, 2003]. Given that spines are postsynaptic sites and that dendrites undergo complex alterations during development [Cline, 2001], it is not surprising that a "subtle" morphological change would cause serious functional consequences.…”

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

“…Observations in post-mortem tissue from individuals with FXS and in the Fmr1 KO mouse have shown that functional deletion of FMRP leads to increased density of filopodia-like and immature dendritic spines (Irwin et al, 2001(Irwin et al, , 2002, suggesting an important role of FMRP for dendritic spine development and maintenance. 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). Different experimental settings, such as age of the mice or neuronal cultures, might explain variations in the observed phenotypes.…”