Trends in Neurosciences
OpinionDo Astrocytes Play a Role in 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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2022, NeuronCitation Excerpt :This process continues throughout postnatal life. Excessive or insufficient synaptic pruning may underlie the psychopathology of multiple complex neuropsychiatric disorders, including ASD, schizophrenia (SCZ), and ID (Cresto et al., 2019; Wang et al., 2018). Studies on genetics in ASD patients have revealed a large number of disrupted genes (Satterstrom et al., 2020).
HDAC inhibitor ameliorates behavioral deficits in Mecp2<sup>308/y</sup> mouse model of Rett syndrome
2021, Brain ResearchCitation Excerpt :Earlier studies suggested the idea that RTT is caused exclusively from loss of Mecp2 function in neurons. Several studies, however, have shown that Mecp2 is clearly expressed in all glial cell types including astrocytes and oligodendrocytes (Ballas et al., 2009; Lioy et al., 2011; Okabe et al., 2012), and that glia, like neurons, are integral components of the neuropathology of RTT (Lioy et al., 2011; Kahanovitch et al., 2019; Cresto et al., 2019; Dong et al., 2020). Though much is known about microtubule organization and microtubule-based transport in neurons, the development and function of microtubules in glia are more enigmatic.
Balancing serendipity and reproducibility: Pluripotent stem cells as experimental systems for intellectual and developmental disorders
2021, Stem Cell ReportsCitation Excerpt :It is unclear to what extent biological differences, technical differences driven by differentiation methods, inconsistent QC and culturing practices, choices of controls, or all of the above, contribute to discrepancies in data from iPSC studies of IDDs. Furthermore, although compelling evidence for altered glial development in IDDs has been reported recently (Cresto et al., 2019; Wong, 2019), this analysis focuses on neural progenitor cells (NPCs) and/or cortical neurons, as these remain the focus of most current IDD-related studies. Literature related to glial differentiation of iPSCs and IDD studies in iPSC-derived glia is presented in Table S2.
Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps
2024, Frontiers in ToxicologyMetabolic dynamics in astrocytes and microglia during post-natal development and their implications for autism spectrum disorders
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