Astrocytes and Developmental Plasticity in Fragile X

Figure 1

The role of astrocytes in FXS. It is becoming increasingly apparent that, in addition to presynaptic terminals and postsynaptic dendritic spines, synapses contain a third element: the fine processes of the astrocyte, which intimately enwrap the first two elements.

(a)   Under normal conditions, astrocytes can promote synaptogenesis via direct and/or indirect contact with neurons through the release of soluble factors. Astrocytes also release a variety of neuroactive substances (gliotransmitters) to modulate synaptic transmission and plasticity. Astrocyte FMRP plays an important role in shaping the neuron morphology and synaptic protein profiles. FMRP has been shown to inhibit translation of specific mRNAs.

(b) In the FXS disease state, nonfunctional FMRP in neurons leads to the dysregulation of synaptic protein synthesis and abnormal dendritic morphologies. FMRP may play a similar role in astrocytes as in neurons, functioning as a negative regulator of protein translation. In FMRP-deficient mice, the inability to repress translation is lost. mGluR5 stimulation, associated with dysregulated FMRP protein levels, results in increased levels of FMRP targeting mRNAs. Basal protein levels encoded by these target mRNAs become significantly elevated and thus improperly regulated. Aberrant spine and dendritic morphology is apparent through increased branching and an abundance of immature spines (filopodial projections).