Abstract
BackgroundFragile X syndrome is the most common inherited form of mental impairment characterized by cognitive impairment, attention deficit and autistic behaviours. The mouse model of Fragile X is used to study the underlying neurobiology associated with behavioral deficiencies. The effect of Fragile X glial cells on the development of neurons has not been studied. We used a co-culture technique in combination with morphometrics on immunostained neurons to investigate the role of astrocytes in the development delays associated with hippocampal neuron development.ResultsWe found that hippocampal neurons grown on Fragile X astrocytes exhibited a significant difference from the neurons grown with normal astrocytes after 7 days in vitro for many parameters including increases in dendritic branching and in area of the cell body. However, after 21 days in culture, the neurons grown on Fragile X astrocytes exhibited morphological characteristics that did not differ significantly from the neurons grown on normal astrocytes. With antibodies to the pre-synaptic protein, synapsin, and to the excitatory post-synaptic protein, PSD-95, we quantified the number of developing excitatory synapses on the dendrites. In addition to the delays in dendritic patterning, the development of excitatory synapses was also delayed in the hippocampal neurons.ConclusionsThese experiments are the first to establish a role for astrocytes in the delayed growth characteristics and abnormal morphological features in dendrites and synapses that characterize the Fragile X syndrome.
Highlights
Fragile X syndrome is the most common inherited form of mental impairment characterized by cognitive impairment, attention deficit and autistic behaviours
Primary hippocampal neurons were isolated from embryonic day 17 animals and seeded above the astrocytes and maintained in MEM supplemented with N2 (Cat No 17502-048, Invitrogen, Burlington, Canada), sodium pyruvate (Cat No 11360-070, Invitrogen, Burlington, Canada) and 6% glucose, for the duration of the experiments
Upon examination of the cultures, no obvious differences could be seen between clusters of neurons grown on Fmr1-/- compared to those grown on WT astrocytes
Summary
Fragile X syndrome is the most common inherited form of mental impairment characterized by cognitive impairment, attention deficit and autistic behaviours. The mouse model of Fragile X is used to study the underlying neurobiology associated with behavioral deficiencies. Abnormal or ‘diseased’ astrocytes are known to be prominent factors in the neurobiology of a number of developmental diseases of the CNS including Fragile X Syndrome (FXS) [3,6,7,8]. Children with FXS suffer from a number of behavioural deficiencies including: mild to severe cognitive impairment, hyperactivity, attention deficit, susceptibility to. The Fmr1-/- mouse has been shown to demonstrate behavioural qualities similar to those seen in individuals with FXS, including: susceptibility to seizures, hyperactivity and learning impairments [15,16,17]. The neurons of Fmr1-/- show abnormal dendritic spine morphology and altered synaptic function [18,19], as documented in humans with FXS [11]
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