Not Just a Bystander: The Emerging Role of Astrocytes and Research Tools in Studying Cognitive Dysfunctions in Schizophrenia

Abstract

Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the brain. Apart from investigating the neural mechanisms underlying schizophrenia, emerging evidence indicates the importance of glial cells in brain structure development and their involvement in cognitive functions. Although the etiopathology of astrocytes in schizophrenia remains unclear, accumulated evidence reveals that alterations in gene expression and astrocyte products have been reported in schizophrenic patients. To further investigate the role of astrocytes in schizophrenia, we highlighted recent progress in the investigation of the effect of astrocytes on abnormalities in glutamate transmission and impairments in the blood-brain barrier. Recent advances in animal models and behavioral methods were introduced to examine schizophrenia-related cognitive deficits and negative symptoms. We also highlighted several experimental tools that further elucidate the role of astrocytes. Instead of focusing on schizophrenia as a neuron-specific disorder, an additional astrocytic perspective provides novel and promising insight into its causal mechanisms and treatment. The involvement of astrocytes in the pathogenesis of schizophrenia and other brain disorders is worth further investigation.

Keywords: animal models; astrocytes; behavioral tasks; blood–brain barrier; cognitive dysfunction; glutamate transmission; glutamate trisynapse; schizophrenia.

Figure 1

Schematic depiction of the cellular constituents of the blood–brain barrier (BBB) and a model of glutamate trisynapses with presynapses, postsynapses, and astrocytes. (A) The BBB is formed by capillary endothelial cells and pericytes and surrounded by astrocytes. The complex tight junctions of endothelial cells and astrocytes contribute to severely restricted penetration and protect against circulating toxins or pathogens in the brain. (B) In glutamatergic trisynapses, glutamate is released from glutamatergic presynaptic neurons and binds to the GluN2 subunit of NMDARs postsynaptically. Meanwhile, the GluN1 subunit of the NMDARs is occupied by D-serine or glycine, which is released from astrocytes as coagonists to activate NMDARs. The activation of NMDAR removes Mg²⁺ and opens the ion channel. In astrocytes, glucose is converted to L-serine via the glycolysis pathway with 3-phosphoglycerate dehydrogenase (PHGDH), and then serine racemase (SR) converts L-serine to D-serine, which is released into the synaptic cleft. D-Serine is also metabolized by D-amino acid oxidase (DAO) to hydroxypyruvate in astrocytes. In addition, astrocytes also participate in the glutamate–glutamine cycle. Glutamate is taken up by astrocytes and readily converted into glutamine by glutamine synthetase (GS). In return, glutamine is released into the extracellular space and taken into presynaptic terminals. Astrocytic adenosine A2A receptors regulate excitatory amino acid transporter expressions and glutamate uptake.

Figure 2

A selection of experimental tools for investigating the role of astrocytes in cognitive deficits in schizophrenia. (The upper panels) Astrocyte-related animal models of schizophrenia, including (from left to right) drug-induced models (such as methionine sulfoximine (MSO) and ceftriaxone injections), genetic mutant mouse models (such as G72, SR, PHGDH, GlyT1 mutant mice, and Gfa2-A2AR knockout mice), GFAP-cre mice, and human iPSC transplantation mice. (The lower left panels) A selection of three behavioral tasks for assessing schizophrenia-like cognitive deficits and negative symptoms in animal models. The puzzle box and object-based attention test (OBAT) can be used to assess cognitive function. Effort-based tasks can be used to measure negative symptoms. (The lower right panels) A selection of four experimental techniques to examine the function of astrocytes. Electrophysiological recording is useful for understanding astrocyte-mediated neuronal transmission and oscillation. Single particle tracking can be used to record the trajectory of receptors or proteins on astrocytic membranes. The specific PET radiotracers ¹⁸F-FDG and ¹¹C-DED quantify astrocyte-related physiological, biochemical, and functional processes. Dynamic contrast-enhanced MRI (DCE-MRI) can be used to assess BBB integrity.