**1. Introduction**

Schizophrenia (SCZ) is a severe mental illness with typical onset during early adulthood, which confers a lifetime disability. The main signs of the disease comprise positive symptoms, such as delusions and hallucinations; negative symptoms, such as blunted emotions, social withdrawal, and apathy; and executive and cognitive neurobehavior interruption. Additionally, SCZ is associated with a greater suicide possibility and a shorter lifetime. The illness puts a substantial socioeconomic burden on caregivers, families, patients, and society [1].

While the mechanisms underlying SCZ remain unknown, dysfunctions in synaptic signaling are implicated. A synapse relying on chemical transmission is comprised of a neural presynaptic and neural postsynaptic component. However, an astrocyte is a vital member of the synapse leading to the term "tripartite synapse" and among other functions, plays a role in synaptic plasticity [2, 3]. Astrocytic processes are considered crucial members of the tripartite synapse because they enclose the pre- and postsynaptic components and are close to the synaptic cleft [4]. They can quickly reuptake excess glutamate produced by the presynaptic terminals because of their great expression of the high-affinity glutamate transporters EAAT1 and EAAT2, which limits excitatory transmission [5]. In turn, astrocytes provide a significant contribution to synaptic plasticity and transmission. Even though they are electrically inactive, they react to presynaptic activation by sending G-protein-mediated Ca2+ signals, which cause the release of "gliotransmitters" such as glutamate, ATP, and GABA, which influence local synaptic transmission [6–8]. The likelihood of inducing LTP is increased by astrocyte-derived glutamate-mediated of NMDA receptor activation on the postsynaptic sites [9]. Furthermore, astrocytic processes surrounding synapses undergo fast structural remodeling due to stimuli that cause synaptic long-term potentiation (LTP), altering their capacity to control synaptic transmission. When taken as a whole, the anatomical and functional data strongly suggest that astrocytes are essential active mediators of synaptic plasticity [10]. Recently, a fourth player at the synapse has been recognized as the important role of the extracellular matrix (ECM), especially in synaptic plasticity has emerged. Accordingly, synapses consist of four pre- and postsynaptic elements, glial processes, and an ECM [11, 12]. In SCZ, it has been shown that interactions between all synapse elements disrupt synaptic functions and alter plasticity [13], and a breakdown in communication between synaptic components and changes in synaptic plasticity is believed to cause SCZ. Given the clinical, genetic, and pathological diversity of SCZ, synaptic dysfunction in specific brain areas may represent a point of convergence, perhaps resulting from various unique molecular processes in different people [13].

The evidence supporting a role of astrocytes in altered synaptic signaling in SCZ is diverse and often includes changes seen in glutamate transmission. Transplanted Human Induced Pluripotent Stem Cell (hiPSC)-astrocyte progenitors from SCZ patients transformed into mature astrocytes in a mouse created behavioral alterations consistent with cognitive and olfactory changes seen in SCZ patients. Healthy neurons co-cultured with astrocytes from SCZ patients of both males and females showed a drastically heightened reaction to glutamate, suggesting modifications in gliotransmitter liberation and/or inadequate turnover of neurotransmitters [14]. Additionally, synaptic dysfunction, demyelination, and alterations in inflammation pathways were noted [14]. Dysregulated glia functions have been associated with endothelial cell stimulation and increased systemic inflammatory markers in brain pathology [15, 16].

Further evidence for a role of altered glutamate signaling in astrocytes playing a role in SCZ are findings that the astrocyte-derived N-methyl-D-aspartate (NMDA) receptor antagonist kynurenic acid (KYNA) is higher in SCZ patients [17, 18]. In addition, KYNA is not only produced in astrocytes but also in a diversity of cell types through activation of the kynurenine pathway (KP) resulting in tryptophan metabolism. As high concentrations of KYNA are associated with the pathophysiology of SCZ, enhanced knowledge of mechanisms leading to high KYNA production in patients with SCZ could aid in the design of novel diagnostics and therapeutics, which could focus on targeting astrocytes [19].

Astrocytes synthesize and release D-serine, which is a co-agonist of the NMDAR where it modulates synaptic activity. Reductions in D-serine release by astrocytes could play a role in SCZ by leading to inhibition of synaptic transmission and synaptic *Astrocytic Abnormalities in Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.106618*

plasticity mediated by NMDA receptors. Hypofunctionality of NMDA receptors has been shown to be associated with behaviors reminiscent of SCZ, and further, a risk factor for SCZ is reduced functioning of NMDAR in cortical pyramidal neurons and interneurons. While astrocytes are not the sole source of D-serine, they do con¬tribute to the available pool, and their contribution can be local and regionspecific. Accordingly, targeting astrocytic D-serine synthesis in SCZ represents a potential clinical strategy in order to reverse cortical hypofunctionality.

Neuroinflammation has been implicated in a role in SCZ, and astrocytes could play a role in this process [20, 21]. These comprise reduced astrocyte cellular characteristics and gene expression in chronic stress, anxiety, depression, and enhanced inflammation in SCZ [22]. Targeting changes in inflammatory markers in astrocytes might also represent a therapeutic strategy for SCZ patients.

In the present chapter, we review molecular aspects of astrocyte abnormality in SCZ, focusing on neuroplasticity in line with clinical features. We also summarize animal studies of the behavioral aspects of this topic. Finally, we propose therapeutic and diagnostic strategies focused on targeting astrocytes.
