**3. Molecular mechanisms**

#### **3.1 Neuroplasticity mechanisms**

#### *3.1.1 Synaptic plasticity and neurotransmitter alterations*

#### *3.1.1.1 Astrocyte function in synaptic plasticity and SCZ*

Patients with SCZ exhibit profound cognitive impairment and negative symptoms resistant to current medication. Evidence supports the theory that these deficiencies are caused, at least in part, by changes in cortical synaptic plasticity, which is the ability of synapses to strengthen or weaken their activity. Targeting synaptic plasticity is a promising therapeutic approach to managing SCZ as synaptic transmission is a well-understood process, and the biochemical mechanisms behind short-term and long-term changes in synaptic strength are becoming even more evident as players at the molecular level are identified [38].

Long-term depression (LTD) and potentiation (LTP) of synaptic transmission are essential processes by which the brain changes the strength of synapses [39]. Many forms of synaptic plasticity depend on alterations in AMPA and NMDA receptors within the membrane, as these excitatory glutamate receptors are essential for synaptic transmission [38]. SCZ brains show reductions in synaptic functioning due to the loss of AMPA and NMDA receptors and loss of dendritic spines and synaptic markers. Loss of synapses and markers is consistent with microscopic analysis in patients showing reductions in brain volume, notably in the hippocampus, prefrontal and superior temporal cortices, and frontolimbic circuitry, which is accompanied with an increase in ventricular size [38].

#### *3.1.1.2 Neurotransmitter hypotheses of SCZ*

The role of dysfunctions in neurotransmitters, many of which are gliotransmitters, has been explored in SCZ and as many of these transmitters are gliotransmitters, alterations in astrocytic functioning have been suggested.

#### *3.1.1.2.1 Glutamate*

Glutamate is the principal excitatory neurotransmitter in the central nervous system (CNS) that initiates fast signal transmission. Its activity is critically

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

involved in routine behaviors, including learning and memory, which mechanistically processes relying on synaptic plasticity. Dysfunctions in glutamate transmission are seen in SCZ [40]. Given the significance of astrocytes in altering glutamatergic transmission, it is probable that they are involved in the glutamate dysfunction seen in SCZ.

Activity of astrocytes regulates extracellular glutamate levels [41]. As high glutamate levels can be toxic, following impulse transmission, EAATs, immediately terminate glutamate transmission by removing glutamate from the tripartite synapse (**Figure 1**). In astrocytes, EAAT1 and EAAT2 are the most prominent EAATs [42]. Once transported into astrocytes by EAATs, glutamate is converted to glutamine-byglutamine synthase. This newly created glutamine can then be transported back to

#### **Figure 1.**

*A general depiction of the position of the astrocyte in the tripartite synapse and BBB. A) Astrocytes protect the brain from blood borne toxins and microbes by close opposition of their end feet on blood vasculature. B) Gap junctions play a crucial role in cellular communications between astrocytes. C) Astrocytes play a vital role in neuronal communication via participation in the tripartite synapse which is shown with important glial and neuronal intracellular and extracellular pathways. Created with BioRender.com. Abbreviations: BBB: Blood brain barrier, D: Dextro, DAO: D-amino acid oxidase, GS: Glutamine synthetase, L: Levo, NMDAR: N-methyl D-aspartate receptor, PHGDH: 3-phosphoglycerate dehydrogenase, and SR: Serine racemase.*

presynaptic neurons in a process known as glutamate-glutamine cycling, where it is converted into glutamate [43].

The glutamate theory of SCZ is based in part on findings that NMDA antagonists like ketamine and phencyclidine induce an SCZ-like psychosis exhibiting positive symptoms [40]. Further evidence of a role played by the NMDA receptor in SCZ is that disruptions in NMDA receptors in interneurons result in the lack of inhibitory signals to glutamate neurons, mainly in the prefrontal cortex, which may be associated with negative symptoms of SCZ [40]. The endogenous NMDAR antagonist KYNA can mimic SCZ-like symptoms similar to other exogenous NMDAR antagonists such as phencyclidine and ketamine. Studies of the role it could play in SCZ have been conducted [19, 44]. At low concentrations, KYNA acts as an antagonist at the strychnine-insensitive glycine-binding site of NMDARs. However, higher concentrations also block the glutamate-binding site of NMDARs [19]. Furthermore, KYNA has modest antagonistic effects on kainate and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate receptors, with concentration-dependent effects on AMPA receptor-mediated actions [19, 44]. In addition, KYNA is an endogenous antagonist of α7 nicotinic acetylcholine receptors, which would also be expected to reduce synaptic excitability. Increased KYNA levels have been noted in the CSF and cortical brain areas in SCZ patients due to alterations in enzyme activity/expression in the kynurenine pathway (KP), which transfers tryptophan metabolism to KYNA synthesis [19, 44].

#### *3.1.1.2.2 Glycine*

Glycine, a nonessential amino acid that plays a critical role in inhibitory and excitatory neurotransmission is upregulated in SCZ. SCZ patients have higher glycine levels, particularly in the parietal and occipital cortex [45]. Astrocytes are a major source of glycine. While thought of as a classic inhibitory amino acid as it interacts with the inhibitory canonical strychnine glycine receptor (GlyR), which is a chloride channel [46], glycine also functions as a potentiator of excitatory transmission by acting as a co-agonist of NMDAR. Interestingly, it is glycine's actions at the NMDAR which appear to play a crucial role in the neurodevelopmental phases of SCZ pathogenesis [47]. D-serine is an endogenous ligand at the NMDAR glycine B-site [48] and has been proposed to activate NMDARs in the amygdala, however, upon high afferent activity glycine released from astrocytes enhanced NMDAR activity, which affected induction of LTP [49].

Glycine concentration in the synaptic cleft is carefully controlled by glycine transporters, particularly GlyT1 and GlyT2, located in astrocytes, which regulate neurotransmitter reuptake. Accordingly, targeting the astrocytic glycine transporters represents a potential treatment for SCZ [50].

#### *3.1.1.2.3 Dopamine and adenosine systems*

Alteration of striatal D2 dopamine receptors leads to positive symptoms, whereas the alteration of the prefrontal cortex D1 dopamine receptor leads to negative and cognitive symptoms. Dopamine transmission within the striatum is also impaired [51]. The number of synapses in the lateral part of the ventral tegmental area and the substantia nigra is reduced in SCZ. Among other effects, loss of synapses would lead to loss of NMDA receptors, which would result in reductions of activity of these striatal dopamine-containing cells, resulting in alterations in dopamine release at terminals. This is supported by findings that there is a deficiency of dopaminergic activation in the prefrontal cortex in SCZ. This could also result from decreased communication between the striatum and the prefrontal cortex, due in part to NMDAR

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

dysfunction that has been shown in both prefrontal cortex and the striatum in postmortem SCZ brain [52].

Adenosine has two known types of receptors: A1 and A2. A1 receptors block the release of neurotransmitters including glutamate. Activating A2A-receptors causes glutamate release, which activates NMDA receptors and inhibits A1-receptors [53]. A2A receptors are found in dopamine-rich locations, such as the prefrontal cortex and the striatum, and their activation causes reduced dopaminergic innervation [53]. Hypofunction of A2A receptors in the striatum leads to hyperfunction of D2 receptors, which are implicated in disorders linked to neuroinflammatory processes, as well as to triggering immunological responses and heightening dopaminergic neurons' vulnerability to neurotoxic injury. Striatal astrocytes express A2A-D2 receptor heterodimers. While D2 receptor activation decreases presynaptic glutamate release, stimulation of A2A receptor reverses this action [53]. Dysfunction of the striatal astrocytic A2A receptor, which causes damage to the D2 receptor and disrupts glutamate homeostasis, is believed to be linked to SCZ [53, 54].

#### *3.1.1.2.4 GABA*

Postmortem investigations have extensively identified changes in various GABArelated markers in SCZ patients. Some studies show the reduction of inhibitory GABAergic neurotransmission across several brain regions affected by SCZ. These anomalies may cause difficulties in emotional functioning and cognitive control. Furthermore, one clinical investigation found reduced GABA concentrations in CSF samples from patients with first-episode psychosis compared to healthy volunteers, which were linked to total and general positive and negative syndrome scale ratings, disease severity, and poor performance on attention testing [55].

Astrocytes react to GABA through various pathways, including GABA receptors and transporters. GABA-activated astrocytes may then influence local neuronal activity by releasing gliotransmitters such as glutamate and ATP. Furthermore, astrocyte activation through various inputs can influence GABAergic neurotransmission. The complexity of communication within the brain is enhanced by reciprocal signaling between GABAergic neurons and astrocytes, and our improved understanding of this complexity could lead to new treatments for brain disorders [55].

#### *3.1.1.2.5 Endocannabinoid systems*

The endocannabinoid system (ECS), which consists of two well-characterized receptors and enzymes responsible for their production and degradation, is engaged in various physiological and pathological processes of the CNS [19].

There are two types of cannabinoid receptors (CBRs), cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), belonging to the family of Gi/o protein-coupled receptors (GPCRs). Therefore, activating them inhibits cAMP production, activates mitogen-activated protein kinases, and presynaptically inhibits several neurotransmitters involved in SCZ through presynaptic mechanisms [56, 57].

CB1Rs are involved in regulation of mood or emotion, antinociception, energy balance, immunological function, and endocrine activities [58]. CB2Rs, on the other hand, are expressed mainly in immunological and hematopoietic cells. CB2Rs have a protective function by reducing inflammation-induced pain via cytokine modulation and immune cell migration [58, 59].

Several alterations in the ECS have been reported in SCZ patients, including changes in CB1R availability, density, and/or mRNA expression, differences in levels of endocannabinoid in specific brain regions and CSF have been noted in SCZ patients. Endogenous CBR ligands are lipid-derived hydrophobic molecules, the best researched of which are N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG). The fatty acid amide hydrolase (FAAH) enzyme quickly metabolizes AEA, whereas the monoacylglycerol lipase (MAGL) enzyme hydrolyzes 2-AG. Blocking the FAAH enzyme in order to heighten effects of AEA has been proposed as a potential therapy for SCZ. Furthermore, phytocannabinoids produced from plants, such as 9-tetrahydrocannabinol (9THC), the main psychoactive component of cannabis, and non-psychoactive cannabidiol (CBD) have intriguingly been suggested as potential treatments for SCZ due to actions involving glutamate release from astrocytes [60, 61]. This is supported by findings that CB1R is located on internal PFC astrocytes and reduces the negative symptoms of SCZ by reducing glutamate release [62]. On the other hand, exogenously applied cannabinoids can induce SCZ-like symptoms in adolescents if exposure is frequent and early in life [62].

#### *3.1.2 Myelination and white matter*

Astrocytes play a significant role in the repair and recovery of neurons, which includes a role in the repair of damage to white matter through their regulation of oligodendrocytes. White matter damage has been linked to developing various demyelinating conditions, including SCZ.

White matter astrocytes differ from those in gray matter in terms of development, morphology, residence, protein synthesis, and the role they play in supporting neighboring cells. During demyelination and remyelination, the functions of astrocytes are dynamic and are modified in response to specific stimuli or reactive processes, leading to vastly different biological outcomes. The effect of astrocytes on oligodendrocytes and various cellular subtypes in the oligodendrocyte lineage includes serving as an energy supply, a modulator of immune system function, a mediator of inflammation processes, a resource for trophic factors, and a regulator of iron. Features of astrocytes that lead to their neuroprotective properties include anti-oxidative properties, stabilization of glutamate homeostasis, and production of growth factors.

Ultrastructural evaluations showed induced microglia near dystrophic and apoptotic oligodendroglia, demyelinating and demyelinating axons, and swollen and vacuolated astroglia in cases with SCZ, in contrast to healthy subjects [15]. Theoretically, targeting astrocyte function represents a rational approach to repair injured myelin white matter-associated diseases such as SCZ [63] and cell therapy using stem cells or progenitor cell-derived astroglia has been recommended for patients with neuropsychiatric disorders associated with white matter degeneration or synaptic loss, [64]. Unfortunately, re-myelinating strategies have to date proved inadequate, which could stem from an unsuitable microenvironment. When taken together, although white matter alterations are implicated in SCZ, the astrocyte-specific alterations in this disease need to be explored further and those alterations need to take into account the vast array of cell types that astrocytes interact with before we can use astrocytic cell therapy for management of SCZ.

### *3.1.3 Adult neurogenesis*

Adult neurogenesis could play a role in the pathological mechanisms of SCZ, but also could perhaps be exploited therapeutically. In the process of adult hippocampal neurogenesis, neural stem cells (NSCs) in the dentate gyrus (DG) transform into neurons, which is a process that continues throughout life [65]. Natural proliferation and

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

maturation of NSCs in DG contribute to emotional behaviors and cognitive function, and disturbances to this process can cause neuropsychiatric disorders such as anxiety, mood disorders, and memory and learning disorders [66–70]. Transformation of NSCs into neurons is regulated by adult astrocytes in the hippocampus [71]. Following transformation, astrocytes contribute to the maturation and integration of neurons in the hippocampal circuit. Inhibiting the exocytosis of astrocytes leads to a decrease in dendritic spine count and dendritic branching, as well as disrupted dendrite survival and maturation of the new neurons [72]. Astrocytes control neurogenesis by releasing a variety of factors. D-Serine, BDNF, fibroblast growth factor 2 (FGF-2), glial cell line-derived neurotrophic factor (GDNF), and VEGF are examples of astrocyte-derived factors that may promote neurogenesis [73].
