Which of the following brain abnormalities is suggested to be a cause of schizophrenia?

17.2.1 Environmental Factors

The etiology of schizophrenia is now thought to be multifactorial, with multiple small-effect and fewer large-effect susceptibility genes interacting with several environmental factors. These factors may lead to developmentally mediated alterations in neuroplasticity, manifesting in a cascade of neurotransmitter and circuit dysfunctions and impaired connectivity with an onset around early adolescence [5]. Several environmental factors, such as antenatal maternal virus infections, obstetric complications entailing hypoxia as a common factor, or stress during neurodevelopment, have been identified to play a role in schizophrenia and bipolar disorder, possibly contributing to smaller hippocampal volumes [6].

Pathogenesis

The etiology of schizophrenia is poorly understood, but accumulating evidence has revealed a wide range of brain abnormalities.6,12 Brain structural abnormalities have been found in postmortem studies and in living subjects by computed tomography (CT) and magnetic resonance imaging (MRI).11,12 Regarding the latter, structural dysmorphologies have included enlarged lateral and third ventricles; loss of total gray matter, frontal, and temporal lobe volume; and a reduction in total brain size. These findings seem to be present at the onset of illness and cannot be attributed to progressive degeneration; however, most findings are nonspecific and are observed in other psychiatric disorders. Functional imaging studies using positron emission tomography (PET) or regional cerebral blood flow have observed decreased metabolism in the frontal cortex (hypofrontality) and left hemisphere dysfunction.

Abnormalities of neurotransmitter systems have also been extensively investigated. For many years, the prevailing theory of schizophrenia has centered on the dopamine system. The dopamine (DA) hypothesis of schizophrenia derived from two observations. First, the potency of standard antipsychotic medication correlates with the amount of D2 receptor blockade. Second, drugs such as amphetamines, which enhance DA activity, can cause a psychosis that mimics paranoid schizophrenia and can exacerbate schizophrenic symptoms. The hypothesis holds that psychotic symptoms such as hallucinations and delusions are associated with hyperactivity of the mesolimbic DA system. Serotonin (5-hydroxytrypamine [5-HT]) and norepinephrine have also been associated with the pathophysiology of schizophrenia because the potency of second-generation antipsychotics has been linked to 5-HT and alpha-adrenergic receptor blockade. Finally, the role of the excitatory neurotransmitter glutamate in the pathophysiology of schizophrenia is gaining greater credence in part because several of the recently identified schizophrenia susceptibility genes target glutamatergic transmission.7,8,14 Agonists of metabotropic glutamate receptors (mGluRs) are currently being investigated as treatments for schizophrenia.15 Metabotropic glutamate receptor agonists actually decrease brain excitability. They also have profound effects on the sleep electroencephalogram (EEG), diminishing REM sleep and non-REM (NREM) fast frequencies in the rat.16

Because no discrete pathologic abnormality has emerged as an etiologic factor, schizophrenia may be an abnormality of neuronal connectivity17 or of integrative neuronal circuits.18 Neither of these theories is inconsistent with the broader and prevailing view that schizophrenia is a neurodevelopmental disorder.19,20 Although abnormal events can occur early in development (prenatal or perinatal), maturational abnormalities can appear during the second decade of life21 or even into middle age.22

Etiologic Factors

Although the etiology of schizophrenia remains unknown, risk factors associated with the development of the disease include both genetic and environmental factors. Schizophrenia is clearly familial. Family, twin, and adoption studies provide strong evidence that schizophrenia is highly heritable. Meta-analysis of twin studies has examined the impact of genes and environment on liability to schizophrenia and estimated genetic heritability to be 81% and shared environmental influences to be 11%.7 Genome-wide association studies suggest that the genetic architecture of schizophrenia may include multiple common variants, each of small effect but acting together to increase the risk of developing the disease; genetic architecture may also include highly penetrant, individually rare variants.8 Because the concordance rate for monozygotic twins only approaches 50%, genetic makeup alone is not sufficient for the development of schizophrenia, and nongenetic or sporadic forms of the disorder must exist.

Environmental factors that might play a role in the etiology of schizophrenia include obstetric complications (e.g., premature birth, low birth weight, preeclampsia, and hypoxia) as well as prenatal or gestational exposure to infection. Seasonality of birth, with winter-spring births as a risk factor for schizophrenia, suggests that maternal influenza infection during pregnancy might compromise fetal brain development. Exposure to other microbial infections (e.g., toxoplasmosis and genitourinary diseases) during the gestational period might also compromise neurodevelopment. Although infections might have direct effects on the fetus, it is more likely that the mother’s immune response to the infection (production of serum antibodies and cytokines) might contribute even more directly to developmental brain damage.9 Although family history and environmental factors may be viewed as separate but contributory risk factors, there is strong evidence that genetic risk and prenatal exposure to infection might interact synergistically to elevate the risk of developing schizophrenia.10 Both etiologic factors—genetic risk and environmental exposure to prenatal infection—are consistent with the prevailing model, which views schizophrenia as a neurodevelopmental disorder.11,12

Dopamine transmission

Three major hypothesis address etiology of schizophrenia are dopamine hypothesis, glutamate hypothesis, and inflammation hypothesis, most influential is classic dopamine hypothesis (Rossum, 1966; Carlsson and Lindqvist, 1963). This hypothesis was essentially based on the observation that all effective antipsychotic drugs provided at least some degree of D2 receptor blockade (Seeman and Lee, 1975; Creese et al., 1976).

Most of the molecular imaging studies target dopamine transmission pathway at different level. 11C-NMSP, 11C-raclopride, and 123I-IBZM target post synaptic D2/D3 receptor. Pooled study shows small increase in D2/D3receptors availability is seen in patients with schizophrenia (Howes et al., 2012). D2/D3 tracers are used to investigate dopamine release in vivo (Laruelle, 1998). The rationale behind using dopamine release study using amphetamine as follows: increase in dopamine following pharmacological application, competes with the radiotracer resulting in a decrease of the amount of binding. It has been found that the decrease in receptor binding is linearly related to the increase in dopamine, providing a unique method to probe dopamine release in vivo. 18F-DOPA PET shows increased presynaptic dopamine synthesis (Howes et al., 2012). No difference has been found in the dopamine transporter, which has been assessed with tracers such as 123I-FP-CIT, 18F-CFT, 123I-β-CIT, and 99mTc -TRODAT 1 (Howes et al., 2012). These studies suggest increased presynaptic output does not appear to be due to higher terminal density (Fig. 1).

Summary of Etiology of Schizophrenia

Considering all available evidence on the etiology of schizophrenia, experts have reached the conclusion that both genetic (inherited) and prenatal (before birth) factors can give rise to a vulnerability to schizophrenia (Walker, Kestler, Bollini, & Hochman, 2004; van Os & Kapur, 2009). The subsequent processes, which affect the development of neurons in the brain, especially those that occur during adolescence and exposure to stressful events, can trigger the behavioral expression of this vulnerability. The etiology of schizophrenia involves the interaction among vulnerabilities within the brain and environmental factors. The illness does not emerge from a single defect in a specific brain region but rather from the dysfunction of different neuronal circuits in multiple brain regions. The brain’s maturational processes play a critical role. As discussed earlier, genetic factors play a large role. The risk increases as the father’s age at the time of conception increases or if one’s biological mother has experienced a serious infection during pregnancy. Some environmental factors do come into play as well. To some extent, urban ethnic minorities are at higher risk, as are immigrants who are not living in their native country. Cannabis (marijuana) use also somewhat increases the likelihood of developing the disorder among those with a genetic vulnerability (van Os & Kapur, 2009). Therefore, schizophrenia is probably “not a single disease entity … it has multiple etiological factors and pathophysiological mechanisms, but common phenotypic features” (Nasrallah, Tandon, & Keshavan, 2011), p. 317). Different genetic and environmental factors cause similar but not identical problems in brain structure and functioning that result in the expression of similar patterns of symptoms that are given the label “schizophrenia.”

Epigenetic regulation in the MAM-E17 model

Recent findings indicate that the etiology of schizophrenia is related to genetic predisposition and environmental factors acting in the early stages of life (Tsuang, 2000) (Fig. 50.1) Environmental risk factors impair gene expression during brain development by affecting epigenetic regulation and inducing an abnormal trajectory of brain maturation (Fig. 50.3). Thus, the identification of epigenetic mechanisms altered during schizophrenia development might be an important target for schizophrenia prevention. Epigenetic regulation is highly dynamic and using animal models might help to understand the epigenetic control of gene transcription during brain maturation (Millan, 2013). Total histone H3 modifications, i.e., methylation, were analyzed in the mPFC of MAM-E17 rats at different stages of development (Mackowiak et al., 2014). The results showed a different trajectory of changes in the dimethylation of histone H3 at lysine 9 (H3K9me2) compared with the trimethylation of histone H3 at lysine 4 (H3K4me3). Prenatal MAM administration affected H3K9me2 levels in adolescence, and no changes were observed in adulthood. In contrast, global H3K4me3 levels decreased only in adulthood. H3Kme3 proteins are present in γ-amino butyric acid (GABA)-ergic cells positive for glutamic acid decarboxylase 67 (GAD67) protein (Fig. 50.4), and a specific reduction in H3K4me3 was found at the promoter of GAD67 gene (Gad1) and PV in MAM-E17 rats that was related to a decrease in the mRNA levels of these genes (Bator, Latusz, Wedzony, et al., 2018; Mackowiak et al., 2019) (Table 50.1). Histone H3 methylation in the mPFC appears to be sensitive to prenatal risk factor action because an increase in global H3K27me3 was observed in the juvenile mPFC of MAM-E17 rats. The observed effect was correlated with an increase in levels of the trimethylation of histone H3 at lysine 27 (H3K27me3) and the transcriptional repressor REST at the proximal promoter region of Grin2b, which might contribute to the decrease in GluN2B protein, an NMDA receptor subunit 2B, in the early stages of postnatal development in the MAM-E17 model (Gulchina, Xu, Snyder, Elefant, & Gao, 2017). Another mechanism of epigenetic regulation, DNA methylation, was also investigated in the MAM-E17 model, and the results showed a decrease in DNA methylation at the gene promoter of cannabinoid receptor 1 (CB1) in the adult mPFC, which correlated with an increase in mRNA and protein levels of CB1 at the same age (Stark et al., 2019). The observed alterations in epigenetic regulation reflect the changes found in postmortem studies in schizophrenia subjects (Millan, 2013), and the expression of genes regulated by this modification is also affected in schizophrenia (Tamminga and Holcomb, 2005).

Table 50.1. The effects of environmental factors in adolescence on behavioral and neurochemical responses in the medial prefrontal cortex in the MAM-E17 model.

↑, an increase; ↓, a decrease; ↔,no change; EE, enriched environment in early adolescence (P23–P29); n.a., not analyzsed; SH, standard housing during postnatal life; SI, social isolation in adolescence (P30–P40).

Environmental factors

Environmental factors may be involved in the aetiology of schizophrenia. There is a higher risk of schizophrenia for people born in winter months (i.e. a 5% increase in risk associated with birth between December and May), and also after viral epidemics, which may affect development in utero. Events that occur during gestation may have an effect on the normal development of the brain, and infections that will affect the mother and indirectly the fetus have a peak incidence in winter and early spring. Obstetric complications (e.g. oxygen deprivation at birth) may also be relevant, in particular in association with a genetic risk.

1.2 Etiology

The current consensus is that the etiology of schizophrenia is multifactorial, resulting from a combination of genetic and environmental factors. Genetic inheritance is believed to account for 50%–80% of the incidence of schizophrenia as evidenced by substantially higher concordance rates in monozygotic versus dizygotic twins (Lewis and Lieberman, 2000). It is manifestly clear that the genetic contribution, albeit a strong one, is complex. No single mutation or genetic variant has been found to be sufficient to cause this disorder. Although genome-wide and single-gene association studies have implicated a long list of candidate genes (Allen et al., 2008), only a small number among these candidate genes have shown to be associated with schizophrenia in many studies and/or to play a biological role that is likely to contribute to the development of this disorder. Genes on that short candidate list include DISC1, neuregulin, ErbB4, reelin, and dysbindin. In addition, recent evidence suggests the association of a small proportion of schizophrenia cases (5%–8%) with de novo copy number variants (CNVs) (Sebat et al., 2009). The lack of a strong association of identified gene candidates with the incidence of schizophrenia may suggest that multiple genes acting in combination through epistasis or synergistically with epigenetic effects may underlie manifestations of this disorder. Some investigators have suggested that the causative gene variants have not been identified at this time because this disease may be caused by rare variants with high penetrance having a large effect (Walsh et al., 2008). Discussion of the studies aimed at gaining a better understanding of the function of schizophrenia candidate genes and how they may contribute to this disorder have been published elsewhere (Jones et al., 2011; Powell et al., 2009).

A “two-hit” developmental model has been proposed in which a combination of environmental and genetic factors affecting early development is responsible for the emergence of the schizophrenia in adolescence/early adulthood (Lewis and Levitt, 2002). Among environmental contributors that have been implicated in the development of schizophrenia, those associated with the neonatal or perinatal period have the strongest scientific support. Prenatal risk factors for schizophrenia include maternal malnutrition and maternal infection. Risk factors associated with the perinatal period have been reported in the medical histories of approximately 20% of patients who suffer from schizophrenia include complication during labor and delivery (e.g., hypoxia) (Lewis and Levitt, 2002; Powell, 2010). Childhood abuse and psychological trauma have also been found to be associated with the development of schizophrenia later in life and, therefore, may constitute risk factors for this disorder (Sideli et al., 2012).

Finally, there is compelling evidence that the use of certain drugs can trigger the onset of schizophrenia or a relapse. Drugs that have been strongly associated with this include stimulants, such as amphetamines, cannabis, and hallucinogens, such as lysergic acid diethylamide (LSD) or phencyclidine (PCP). However, it has been hard to establish a clear causal connection between drug use and schizophrenia as well as the extent that drug use can trigger schizophrenia because it is likely to occur only in people with an underlying biological predisposition for the disorder (Hermens et al., 2009; Yui et al., 1999).

Publisher Summary

This chapter discusses some implications for the etiology of schizophrenia. Genetic studies provide indirect support for the idea that an impairment of noradrenergic function may be involved in schizophrenia. Several lines of biochemical evidence suggest that 6-hydroxydopamine is the aberrant metabolite that causes schizophrenia. This compound is an autoxidation product and metabolite of dopamine and its formation can occur to a significant extent in the intact animal. 6-Hydroxydopamine induces a specific degeneration of peripheral sympathetic nerve terminals with a marked and long-lasting depletion of norepinephrine. It is found that when injected intraventricularly into the rat brain, 6-hydroxydopamine similarly causes a prolonged or permanent depletion of brain catecholamines. Only catecholamine-containing neurons are affected, and brain norepinephrine is more severely depleted than dopamine. Electron microscopic evidence reveals that norepinephrine nerve terminals in the brain degenerate and eventually disappear after repeated doses of 6-hydroxydopamine. Single doses of 6-hydroxydopamine of 200 μg or less, however, may decrease brain norepinephrine without apparent ultrastructural damage. It is found that despite the profound damage to central noradrenergic neurons, rats treated with 6-hydroxydopamine are reported to be grossly indistinguishable from controls except for a slight decrease in body weight and a lack of self-grooming.

Other Candidate Genes

Several chromosomal regions have strong linkage and associations with schizophrenia. At least nine regions associated with schizophrenia have been identified; these include chromosomes 6p22-p24, 6q21-q25, 1q42, 1q21-q22, 13q32-q34, 8p21-p22, 22q11-q12, 5q21-q33, and 10p11-p15. Two of these are supported in multiple studies: chromosomes 8p and 22q. Chromosome 8p21-22 has been discussed above with neuregulin. Deletions of chromosome 22q11 account for associations in a smaller set of individuals with schizophrenia. Candidate genes in this region include those for catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and a zinc finger–DHHC domain (ZDHHC8). COMT participates in catecholamine degradation. A V158M mutation affects the activity and stability of the enzyme and is seen in decreased frontal lobe function tests for some individuals. Data are mixed for schizophrenic individuals but continue to support this finding in certain populations. SNP haplotype analysis (see Chapter 13) demonstrates strong association within specific populations for mutations in this gene.

The focus of many hypotheses about the etiology of schizophrenia and bipolar disorder is that there is a defect in GABAergic signaling. Studies demonstrate that down-regulation of two genes, reelin (RELN) and glutamic acid decarboxylase (GAD1) in telencephalic GABAergic neurons of schizophrenic patients correlates with increased expression of a DNA methyltransferase (DNMT1) responsible for methylating cytosines in promoter CpG islands. Decreased expression of RELN and GAD1 leads to decreased conversion of glutamic acid to GABA. However, it is unclear whether these results are contributory to schizophrenia or a consequence of the disease.

Neurology

Another area of focus is the metabolism of dopamine by catechol-O-methyltransferase in schizophrenia and bipolar disorder, since an imbalance of dopamine is considered key in the pathogenesis of psychosis. As noted above, COMT is located in a region deleted in VCFS, a syndrome with increased risk for schizophrenia. This enzyme catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine (Fig. 8-21). Genetic variation producing reduced levels of this enzyme is also associated with decreased prefrontal cortical function, a finding in schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder (ADHD), panic disorder, phobias, obsessive-compulsive disorder, and anorexia nervosa. Other similarities or related dissimilarities are seen in studies of families with independently occurring schizophrenia and bipolar disorder. Chromosomal studies implicate similar abnormalities in both disorders. Dopamine expression is affected similarly in both disorders, and several genes in the dopamine pathway are being investigated intensely. Likewise, the dopaminergic pathway is of considerable interest to investigators for other disorders. Along with Parkinson disease, which has already been discussed, dopamine is hypothesized to play a role in ADHD and Tourette syndrome as well. Both schizophrenia and bipolar disorder demonstrate elevated levels of vesicular monoamine transporter (VMAT2 protein; SLC18A2 gene) in the brainstem. This protein regulates neurotransmitter transport but is distributed differently in brains affected by the two disorders. Its proper function is essential for correct activity of the monoaminergic systems, and it is the site of action of several drugs, including reserpine and tetrabenazine. Finally, the left side of the hippocampus is larger in brains affected with bipolar disorder, but the hippocampus is smaller in schizophrenia-affected brains.

Pharmacology