Rethinking Intellectual Disability from Neuro- to Astro-Pathology

Abstract

Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under neuronal control. However, this vision has recently evolved into a more integrative conception in which astroglia, rather than just acting as metabolic supply and structural anchoring for neurons, interact at distinct levels modulating neuronal communication and possibly also cognitive processes. Recently, genetic tools have made it possible to specifically manipulate astrocyte activity unraveling novel functions that involve astrocytes in memory function in the healthy brain. However, astrocyte manipulation has also underscored potential mechanisms by which dysfunctional astrocytes could contribute to memory deficits in several neurodevelopmental disorders revealing new pathogenic mechanisms in intellectual disability. Here, we review the current knowledge about astrocyte dysfunction that might contribute to learning and memory impairment in neurodevelopmental disorders, with special focus on Fragile X syndrome and Down syndrome.

Astroglial and microglial pathology in Down syndrome: Focus on Alzheimer's disease

“…Astrocytic dysfunction might interfere with neuronal excitability and the balance of excitatory and inhibitory transmission (Cresto et al, 2019 ). Such dysfunction could contribute to learning and memory impairments observed in DS (Fernández-Blanco and Dierssen, 2020 ).…”

Astrocyte: A Foe or a Friend in Intellectual Disability-Related Diseases

“…As for the environmental factors, malnutrition, brain trauma, maternal perinatal infection, and early childhood CNS infection may cause an intellectual impairment ( Purugganan, 2018 ). Several genetic diseases, including DS and FXS, are considered to be caused by neuronal changes ( Fernández-Blanco and Dierssen, 2020 ). With an in-depth investigation of astrocytes, the pathological roles of astrocytes in neurodevelopmental disorders have been continuously explored, suggesting that changes in astrocytes may play an important role in the pathogenesis of ID.…”

Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome

“…For many decades, neurons have been the central focus of studies aiming to better understand the mechanisms underlying the cognitive impairment and the neurodevelopmental and neurodegenerative aspects of DS. In recent years, the recognition that other brain cell types, especially astrocytes, have crucial roles in the maintenance of proper brain development and function, including neuronal integrity, has opened new avenues in neuroscience and DS research [ 6 , 7 ].…”