Trends in Neurosciences
Volume 42, Issue 8, August 2019, Pages 518-527
Journal home page for Trends in Neurosciences

Opinion
Do Astrocytes Play a Role in Intellectual Disabilities?

https://doi.org/10.1016/j.tins.2019.05.011Get rights and content

Highlights

  • The clinical spectrum of intellectual disability (ID) varies widely and is estimated to affect 1%–3% of the population. Genetic evidence indicates that ID-related proteins are enriched at synaptic compartments, giving rise to the concept of synaptopathies.

  • Astrocytes are now considered an essential, ‘third element’ of the synapse (complementing the pre- and postsynaptic compartments). Astrocytes play important roles in synapse formation, maturation, and elimination, as well as being regulators of synaptic activity. Despite this multipartite picture of the synapse, relatively few studies have addressed the contribution of astrocytes (and more generally, glia) in ID.

  • Recent studies have begun to shed light on the mechanistic roles of astrocytes in ID using animal models of Rett, Down, and fragile X syndromes.

  • Studying the roles of astrocytes in ID is a promising strategy to unravel the pathophysiological mechanisms involved in the development of ID.

Neurodevelopmental disorders, including those involving intellectual disability, are characterized by abnormalities in formation and functions of synaptic circuits. Traditionally, research on synaptogenesis and synaptic transmission in health and disease focused on neurons, however, a growing number of studies have highlighted the role of astrocytes in this context. Tight structural and functional interactions of astrocytes and synapses indeed play important roles in brain functions, and the repertoire of astroglial regulations of synaptic circuits is large and complex. Recently, genetic studies of intellectual disabilities have underscored potential contributions of astrocytes in the pathophysiology of these disorders. Here we review how alterations of astrocyte functions in disease may interfere with neuronal excitability and the balance of excitatory and inhibitory transmission during development, and contribute to intellectual disabilities.

Section snippets

Intellectual Disabilities

Intellectual disabilities (ID) (see Glossary), also called learning disability, mental retardation, or cognitive deficit, are defined by an overall intelligence quotient (IQ) lower than 70, associated with deficits in conceptual, social, and practical adaptive skills, with an onset before the age of 18 years. The clinical spectrum of cognitive deficit varies widely, from non-syndromic ID to autism spectrum disorder (ASD), and is estimated to affect 1 to 3% of the population. The causes of ID

Neuropathies: A Restrictive Vision of ID

Expression of genes involved in ID, initially viewed as mainly confined to neurons, was recently described in astrocytes, suggesting that deficient astrocytes contribute to ID [3]. RNA sequencing technologies of brain cells 4., 5. revealed that most ID genes [6] are indeed expressed not only in neurons but also in astrocytes (about 70% of ID genes). These genes encode for proteins enriched in mitochondria and lysosomes, and that play roles in oxydoreduction functions known to be altered in

Neuronal Morphological Alterations Resulting from Astroglial Dysfunction

A common feature of most IDs is altered neuronal morphology. Reduced dendritic branching, long thin immature spines, and reduced spine motility have indeed been reported in FXS, RS, and DS, suggesting that synaptic networks remain in an immature state 35., 36., 37.. Interestingly, recent data indicate that astrocytes are involved in the formation and maturation of neuronal networks by acting at multiple levels, such as dendritic growth, synaptogenesis, synapse maintenance, and pruning 38., 39..

Concluding Remarks and Future Perspectives

Genetically linked IDs, including DS, RS, and FXS, are now well recognized in presenting neuronal alterations at the synaptic level. More recently, glial dysfunctions have also been reported in such diseases, yet their contribution remains elusive (see Outstanding Questions). Only in a few cases, for instance FXS and RS, have astrocyte dysfunctions been directly shown to contribute to synaptic defects. These defects relate, in particular, to the formation of excitatory synapses, dendritic

Acknowledgments

This work was supported by grants from the French National Agency for Research (grant # ANR-15-CE16-0019-01) to P.B. and N.R., from the Jerome-Lejeune Foundation (grant # 1415) to P.B., from the European Research Council (consolidator grant #683154), European Union’s Horizon 2020 research and innovation program (H2020-MSCA-ITN, grant #722053, EU-GliaPhD) and Jerome-Lejeune Foundation (grant #1535) to N.R., and from French Research Ministry (BioSPC doctoral school, Paris Descartes University) to

Glossary

GABA switch
neurodevelopmental phenomenon where NKCC1 activity decreases whereas KCC2 activity increases, leading to an inversion of the Cl gradient. This inversion explains the transition of the effects of GABA on neuronal activity, from depolarizing during early development to hyperpolarizing at later stages.
Intellectual disability (ID)
neurodevelopmental disorders characterized by a low intellectual quotient associated with deficits in adaptability, including sociability, conceptualization,

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