*3.1.3.3 Lactate and VEGF*

Astrocytes store large amounts of glycogen as a source of energy for cells [79]. Astrocytes break down glycogen into lactate that is released from cells by a monocarboxylate transporter 4 (MCT4). The neurotransmitter MCT2 takes lactate up as an energy source for neurons. This pathway is called the astrocyte-neuron lactate shuttle [80, 81].

Increasing lactate concentrations in the blood can raise brain VEGF levels by binding to the hydroxycarboxylic acid 1 receptor, which presents on vascular endothelial cells [82]. Then the VEGF stimulates angiogenesis and neurogenesis. Intraperitoneal administration of lactate to mice increases abGC viability via MCT2 [83], however, further research is needed to understand how increased lactate mediates this action on neurogenesis.

#### **3.2 Immune mechanisms**

#### *3.2.1 Innate immunity*

Individuals affected by neuropsychiatric conditions usually present with hyperinflammation-associated dysfunctions in the peripheral blood, such as raised concentrations of inflammatory cytokines or chemokines, augmented quantities of circulating monocytes and neutrophils, along with a higher reactivity of astrocytes, microglia, as well as brain endothelial cells to different proinflammatory signals [84].

Due to the prominent role of inflammation in neuropsychiatric conditions, it is important to understand the role of inflammasomes. These essential multimeric complexes regulate inflammation by mediating the secretion of cytokines. Specifically, inflammasome pathways can be categorized into canonical and noncanonical signaling, which depend on caspase-1 and caspase-4/5 activation in humans, respectively [85]. Caspase-1 activation helps the maturation of IL-1β and IL-18, two vital inflammatory cytokines. Two neuroimaging studies also showed a link between carrier status for a functional single nucleotide polymorphism (SNP) in the IL-1β gene and aberrant white and gray matter proportions in SCZ patients, unlike healthy patients individuals [15]. Researchers also found that orbitofrontal white matter neuronal compactness was enhanced in SCZ cases with high transcription concentrations of proinflammatory cytokines compared to those with low concentrations [15]. In another study, the animals presented SCZ-like neurobehavior at 45 postnatal days linked with the increase of NLRP3 inflammasome expression and IL-1β levels on 7, 14, and 45 postnatal days [86]. This study shows maternal immune activation (MIA) may be associated with an SCZ-like neurobehavior. This neurobehavior can be induced to a neuroinflammatory profile in the brain. This evidence may base future studies on the relationship between neuroinflammation and psychiatric disorders [87].

Extracellular adenosine triphosphate (ATP) and the metabolite adenosine are key mediators of the immune response. Excess shedding of ATP into the intercellular area from induced/injured nerve cells or abnormal purinergic signaling induces the nod-like receptor proteins (NLRPs) of inflammasomes in astrocytes/microglia [84]. A new review article details the involvement of aberrant purinergic signaling in the pathogenesis of SCZ, in addition to other neuropsychiatric disorders such as major depressive disorder, bipolar disorder, autism, anxiety, and attention-deficit/ hyperactivity disorders (ADHDs) [88]. Each of these conditions could be attributed to abnormalities in signaling from P1 and P2 receptors along with enzymes processing the metabolism of purinergic mediators.

In addition, SCZ patients are often treated with antipsychotic medications that cause brain volume reduction and astrocyte expiry in a process called pyroptosis or proinflammatory cellular expiry [89]. This process involves the formation of inflammatory bodies and enhanced production of complexes such as NLRP3, parallel with the induction of caspases and gasdermin D (GSDMD). These components are strongly linked to innate immunity, hyperinflammation, and cell damage/expiry.

#### *Astrocytic Abnormalities in Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.106618*

The same study found the main effect of antipsychotic treatments on astrocyte pyroptotic pathways and the molecular processes that could be exerted through inflammasome pathways [89]. In this experiment, 72-h therapy with olanzapine, quetiapine, risperidone, or haloperidol strongly attenuated the astrocytes' viability. 24-h therapy by olanzapine, quetiapine, risperidone, or haloperidol dose dependently augmented the protein synthesis of astrocytic NLRP3, NLRP6, caspase-1, caspase-4, and GSDMD. Co-administration with a histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine (FMPH), attenuated the raised synthesis of NLRP3, caspase-1, and GSDMD activated via olanzapine, quetiapine, risperidone, or haloperidol [89]. Moreover, olanzapine, quetiapine, risperidone, or haloperidol treatment-induced pore formation in the astrocyte membranes was suppressed via FMPH co-treatment [89].

When taken together, astrocytic inflammasomes and hyperinflammation are implicated in SCZ, and activation of astrocyte pyroptotic pathways could be due to antipsychotic-activated astrocyte expiry. Further, H1 receptor activation could be a robust therapeutic approach to inhibit antipsychotic-activated astrocyte pyroptosis and hyperinflammation [90]. However, more studies should assess astrocyte-specific (or other CNS cell-specific) inflammasomes and consider the noncanonical pathways to understand more fully how these innate complexes contribute to hyperinflammatory cytokine secretion and neuronal/glial damage. Also, various toll-like receptors (TLKs) are involved in SCZ. These receptors are essential as they bridge innate and adaptive immunity and interact with inflammasomes. More studies are needed to decipher the role of astrocyte-specific TLRs in SCZ patients.

## *3.2.2 Adaptive immunity*

Adaptive immunity, which arises following activity of the innate immune system, occupies a pivotal function in neurodevelopment [91]. A key component of the adaptive immune response is specialized immune cells known as T lymphocytes (T cells). The ability of T cells to penetrate the brain, stimulate microglia, and cause neuroinflammation is widely established, and these activities have been shown to disrupt several brain functions and cause progressive neuro alterations [92, 93]. While a role of inflammatory states has been noted in SCZ [94, 95], the impact of the adaptive immune system, particularly T lymphocyte cells, on the essential characteristics and severity of SCZ is unknown; however, epidemiological, immunological, and gene expression research do suggest a degree of dysfunction of T cells-related processes in SCZ [95–98]. Higher concentrations of T cells in the hippocampus and an elevated number of activated lymphocytes in the CSF have been noted in SCZ patients suggesting blood-brain barrier disruption and T-cell infiltration [99]. Multiple genome-wide association studies (GWAS) have noted genetic variations in SCZ patients of CD28 and CTLA-4 genes, which code for regulatory molecules of the adaptive immune system suggesting that these proteins modulate T-cell activity and are associated with T-cell functions, including antigen processing and cell adhesion, this provides further evidence that the adaptive immune system plays a role in SCZ [100, 101].

SCZ is linked to modestly elevated blood cytokines, which are thought to be the result/stimulus for the activation of microglia [102]. Overlap between activated microglia, proinflammatory cytokines, and translocator protein (TSPO) leads to the basis of using TSPO-PET imaging to monitor neurodegeneration. In SCZ patients, findings of lower levels of TSPO in frontal and subcortical regions, including caudate, putamen, and thalamus, lead to the speculation that suppression of microglial inflammation results in reduced TSPO binding [103]. However, discrepancies that exist in this literature and utility of this technique in SCZ have been debated given differences in degeneration seen in SCZ when compared to other neurodegenerative diseases [104, 105]. The discrepancy between experiments that show an increase, decrease, or no change in TSPO in the subcortical regions of schizophrenic patients has prompted several follow-up investigations employing first and second-generation tracers with mixed results [106, 107].

Postmortem immunohistochemistry analysis, genetic association studies, and transcriptome investigations indicate increased astrocyte activity in SCZ [29].

The expression of marker gene profiles of various cortical cell types was investigated in a prior study, which gave compelling evidence of an increase in astroglial gene expression in SCZ [108].

Further studies strengthened these results and suggested that increased astroglial gene expression followed by a decrease in microglial gene expression is a primary cause of disease rather than a side effect [109, 110].

Astrocytes play a significant role in microglial excitation and function via TGF-β. TGF-β regulates microglial previous studies discovered that TGF-β regulates microglial activation and activity, and astrocytes are crucial actors in this process [111–113]; A critical process that actively suppresses the inflammatory TSPO-expressing phenotype of microglia via elimination of the TGF-β receptor type 2 from adult microglia could be pertinent to the SCZ patient debate [111].

#### **3.3 Other mechanisms**

#### *3.3.1 Gap junction*

Connexins make gap junction channels that facilitate the transmission of intercellular calcium currents. Most brain gap junctions are situated among glial cells and gap junctions between astrocytes and astrocytic processes are known as reflexive gap junctions and together an astroglial system is created [114]. Gap junctions allow two-sided interchange of molecules, ions, nutrients, etc. The gating of brain gap junction channels is modulated dynamically by alterations in the number of cell connections, conductance properties, and subunit configurations. Astrocyte signaling happens primarily via intercellular calcium currents in response to neuronal activity and/or through flux in the endoplasmic reticulum.

Gap junctions comprise hemichannels (connexons) that attach through their extracytoplasmic processes. Each hemichannel is an oligomer of six connexin proteins (Cx). An astrocytic syncytium gap junction is comprised of four connexins, Cx32, Cx26, Cx43, and Cx45, which can create homotypic (*i.e.,* gap junction channels created by hemichannels of the identical type) or heterotypic gap junction channels (*i.e.,* created by hemichannels of various types) [115].

Loss of gap junction function in astrocytes has been hypothesized to play a role in SCZ [116]. Use of computational modeling of astrocyte gap junction activity also supported the conclusion that a loss of astrocytic gap junctions would alter activity in the neural network which could play a role in neuronal-glial changes seen in SCZ [117]. Finally, reduced gap junctions between astrocytes were found to concentrate signaling among the most connected astrocytes, which would be expected to impact communication at the tripartite synapse [118] that could lead to cognitive deficits.
