Astrocytes are widely distributed in the brain and are characterised as the largest glial cells in size, and their number in the brain is greater than the neurons (Sofroniew and Vinters, 2010). They are known as astrocytes because they resemble the stars. Astrocytes evolved from the original neural progenitor cells and then differentiated into two types of cells based on their different distributions in the brain: fibrous and protoplasmic astrocytes (Miller and Raff, 1984). Fibrous astrocytes are slender with few branches mainly distributed in the white matter of the brain marrow. Furthermore, fibrous astrocytes contain many glial filaments comprising glial fibrillary acidic protein (GFAP). However, protoplasmic astrocytes have more cytoplasmic branches and fewer glial filaments, which are mainly distributed in the grey matter (McGann et al., 2012). Based on single-cell sequencing, a recent study suggested that astrocyte might contain multiple subtypes with transcriptomic differences (Batiuk et al., 2020). These subtypes were brain region-specific with distinct morphological and physiological functions (Batiuk et al., 2020).

Astrocytes have molecular marker specificity. The GFAP is a specific molecular marker protein of astrocytes (Sticozzi et al., 2021). GFAP expression is closely associated with the astrocyte activation; therefore, the GFAP can be used as a reliable and sensitive marker of reactive astrocytes (Liddelow and Barres, 2017). Furthermore, S100β is an acidic calcium-binding protein synthesised and released by astrocytes that mainly affect the growth, proliferation and differentiation of glial cells (Donato et al., 2013). Similar to the GFAP, S100β is also considered a molecular marker of astrocytes (Cox et al., 2018). Upon astrocyte activation, the S100β expression also increases (Shobha et al., 2010). Vimentin (Vim) is also a member of the intermediate filament family (Terriac et al., 2017)and rarely expressed in astrocytes under normal conditions. However, in damaged CNS, the Vim expression will increase in reactive astrocytes, making Vima molecular marker of astrocytes (Ivaska et al., 2007). These molecular markers provide an important basis for investigating the roles and changes of astrocytes in the pathological state of the CNS.

Intellectual disability (ID) is a neurodevelopmental disease characterised by intellectual function and adaptability defects usually occurring during the developmental stages of neurons (Purugganan, 2018). It is the most common concomitant symptom of many diseases, such as Rett syndrome (RS), Down’s syndrome (DS), and fragile X syndrome (FXS) (Purugganan, 2018; Romano, 2022). The overall intelligence quotient of patients with ID is < 70 (Shea, 2012). Neuron growth retardation is the main cause of ID. In previous studies, neuronal morphology and functional changes were believed to be major factors inducing ID (McGann et al., 2012). In recent years, with the continuous research on astrocytes, astrocytes are found to play an important role in affecting the function of neural development (Cresto et al., 2019). Gene sequencing results in patients with ID show that a large number of ID-related genes are specifically expressed in astrocytes, not in the neurons (Lelieveld et al., 2016), suggesting that astrocytes, like neurons, are also important ID regulators.

Previous studies have suggested that astrocytes mainly develop around the neurons, and their processes can extend and fill the cell body and neurite to support and separate the neurons. In some astrocytes, the end process becomes the end feet, making it easier to adhere to the capillary wall or brain and spinal cord surfaces to form glial-limiting membranes (Hanani and Verkhratsky, 2021). With the continuous investigation of astrocytes, they have been found to regulate the central nervous system (CNS). Astrocytes can establish two-way communication with the neurons, participate in synaptic composition (Kofuji and Araque, 2021), respond to neurotransmitters released by synapses (Durkee and Araque, 2019), and become reactive upon chemical or physical insult. They could also be activated by the microglia and regulate neuronal and oligodendrocyte deaths (Liddelow et al., 2017). These reactive astrocytes are also involved in synaptic formation and clearance and synaptic plasticity regulation (Van Horn and Ruthazer, 2019). Furthermore, astrocyte ion channels are also involved in the neurotransmitter and ion metabolisms, such as glutamate and adenosine triphosphate (ATP) (Sofroniew and Vinters, 2010), regulating the neuronal excitability and maintaining the blood–brain barrier (Halassa et al., 2007). Taken together, these studies indicated that reactive astrocytes play a complicated role in the pathogenesis of ID. Therefore, this mini-review aimed to investigate the morphology and functional changes of reactive astrocytes in ID-related diseases and discuss the possible effects of drugs on the astrocytes.

The factors causing ID can be divided into genetic and environmental (Table 1). Regarding the genetic factors, various genetic syndromes can result in intellectual impairment, such as DS, caused by chromosomal variation (another chromosome 21) (Chen et al., 2014), Williams syndrome caused by deletion of the region near the long-arm chromosome 7 (7q11.23) (Neuman and Henske, 2011), FXS caused by FMR1 gene defect and its protein product deletion (Pacey et al., 2015), RS caused by the MECP2 gene mutation on the X chromosome (Andoh-Noda et al., 2015), and tuberous sclerosis (TS) caused by TSC1 and TSC2 gene mutations (Neuman and Henske, 2011). 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.

From an in-depth investigation of the morphology and function of glial cells, the significance of astrocyte morphological and functional abnormalities to the occurrence of intellectual impairment gradually emerged (Cresto et al., 2019). For example, early experiments showed that RS was caused by the MeCP2deletion in neurons (Giacometti et al., 2007; Guy et al., 2007); however, in a recent study, Ballas et al. (2009) reported that MeCP2 deletion was also observed in astrocytes and that MeCP2-deleted astrocytes could not support the normal neuronal growth. By coculturing neuronal cells with FXS astrocytes, Jacobs et al. (2010) found that FXS astrocytes can delay dendritic and synaptic growth. Similarly, Cheng et al. (2016) also demonstrated that neurons showed morphological defects and changes in the synaptic formation of the dendritic spines when neuronal cells were cocultured with FXS astrocytes. In the Fmr1 knockout mouse model simulating FXS, dendritic developmental changes can also be observed (Hodges et al., 2017). Similarly, DS astrocytes are also toxic to neurons in vivo and in vitro (Chen et al., 2014). These experiments showed that astrocytes are closely associated with the development and formation of neurons and the occurrence of ID-related diseases, although the roles of astrocytes in ID should be further investigated.

Five approaches have been used for ID management: physical, training, psycho-, dietary, and drug therapy. This mini-review focuses on drug treatment. Multiple drugs have already been used for the treatment of mental disorders, such as piracetam, aniracetam, monosialotetrahexosylganglioside sodium (GMI), mecobalamin, vitamin B12, and methylphenidate hydrochloride.

Cetam drugs can reverse the effects of scopolamine of reducing glucose utilisation in the cerebral cortex (Piercey et al., 1987). In the Alzheimer’s disease model, mitochondrial ATP production and membrane potential were enhanced after the piracetam treatment, which reduced apoptosis and finally enhanced neuronal plasticity (Leuner et al., 2010). Simultaneously, studies have shown that cetam drugs can slow down the inactivation of the AMPA receptor (Jin et al., 2005) and increase the calcium level in astrocytes (Marisco et al., 2013). Slowing the AMPA receptor inactivation can also block the potassium current in astrocytes by increasing an endogenous Na⁺ level (Robert and Magistretti, 1997) and protect against the toxicity caused by neuronal overexcitation. Cetam drugs can also reduce the oxidative stress damage in astrocytes (Gabryel et al., 2002) and reduce the GFAP and reactivity of astrocytes (Pimentel et al., 2009) to improve patients’ memory and brain function (Malykh and Sadaie, 2010).

Monosialotetrahexosylganglioside sodium (GMI) is an important component of the mammalian nerve cells (Wang et al., 2021) and can partially prevent an abnormal release or reuptake of excitatory amino acid neurotransmitters, such as glutamate (Zhang et al., 2015); thus, it can inhibit excessive glutamate expression from damaging brain nerves and tissues (Hinzman et al., 2012). GMI can also improve cerebral blood circulation, increase blood oxygen, protect neurons (Aureli et al., 2016) and reduce N-methyl-D-aspartate-dependent excitotoxicity from astrocyte morphological swelling (Häussinger and Schliess, 2005).

Vitamin B12 was needed for nerve development (Selhub et al., 2000). Reactive astrocytes were increased in the grey matter of vitamin-B-deficient rats, accompanied by microglial oedema and myelinolytic lesions (Scalabrino, 2009). Mecobalamin and vitamin B12 can supplement vitamin B12 in the brain; promote nucleic acid and protein synthesis; enhance axonal transportation, axonal regeneration, and myelin formation to prevent axonal degeneration; repair damaged nerve tissues; and improve the damaged glial cells in the brain (Wu et al., 2019).

Furthermore, a previous study reported that the antibiotic minocycline can partially correct the pathological phenotypes of astrocytes by specifically regulating the S100β, GFAP, inducible nitric oxide synthase and thrombospondins 1 and 2 expressions in DS astrocytes (Chen et al., 2014), which may provide a new treatment for DS.

With an in-depth investigation of astrocytes in recent years, their roles in neural development have been gradually explored. Their changes are also closely associated with the occurrence and progression of many neurological diseases. The aetiology of ID is complex, and several mechanisms remain unclear. Therefore, this mini-review shows that functional changes of astrocytes under the action of various pathogenic factors are closely related to ID, and various drugs for ID can also attenuate astrocyte lesions to varying degrees. However, a few effective drugs have been administered for functional changes of astrocytes under pathological conditions to treat ID-related diseases. This suggests that morphological and functional changes of astrocytes may be one of the important mechanisms of these diseases. Dissecting the contribution of distinct astrocyte subtypes to ID-related diseases might provide a potential therapeutic approach and benefit these patients. Therefore, drugs that inhibit astrocyte lesions may become a new and important treatment strategy for ID in the future.

BW and LZh wrote the manuscript. BW, LZo, ML, and LZh reviewed the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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