A review of the Evolution of the Pathogenesis of Schzophrenia

Nichelle Jackson B.S. , Department of Biology, Howard University

Abstract

Historically, individuals suffering from psychiatric disorders, like schizophrenia, were mistreated due to a lack of understanding of the disease. This led to incorrect theories in the origins and treatments of psychiatric disorders. While the cause of schizophrenia remains unknown, the attention and attitude towards mental illness has drastically improved within the last century. Currently, schizophrenia is understood as a highly heritable psychiatric disorder with environmental risk factors. Patients diagnosed with schizophrenia disorders exhibit a variety of symptoms including, but not limited to, hallucinations, delusions, thought and movement disorders, speech impediments, in addition to, deficits in executive functioning, working memory, attention and affect. While roughly 1% of the world’s population is diagnosed with schizophrenia, the adverse impact extends beyond the individual to family and society. Theories regarding the cause of schizophrenia range from gene-environment interactions to differences in brain chemistry and structure. Much research has been done to identify the role of single gene mutations in the onset schizophrenia. Disrupted-in-schizophrenia-1 is among the most prominent candidate gene characterized.  
      Evolutionary theories suggest schizophrenia, and other psychiatric disorders, are uniquely human disorders that may have coevolved during the evolution of the human brain. As brain size and complexity, relative to body mass increased, the energetic demands also increased. Some evidence suggests the increased energetic demand during brain evolution led to a greater demand of mitochondria. Furthermore, the requirements to establish processes and pathways that led to advancement in cognition, language and executive functioning, may have functioned as a double-edged sword that resulted in novel psychiatric disorders. Therefore individuals with schizophrenia may exhibit a dysfunction in the coevolution of mitochondria in response to greater energetic needs. Currently, a variety of techniques using rodent models and comparative genetics are utilized to investigate the cause, pathophysiology, and therapeutic targets of schizophrenia while simultaneously placing this disorder into an evolutionary perspective. 

Introduction

Throughout history, individuals with psychiatric disorders were stigmatized, dehumanized and separated from the community. During the Middle Ages, there was no differentiation between mental disorders and all those afflicted by an illness were thought to be either possessed by demons or punished by gods. To treat these disorders, individuals were subjected to blood-lettings, exorcisms and burning at the stake. By the 19th century, psychiatric disorders were still not understood, but the illness was viewed as a sickness rather than an evil or divine punishment. During this time, the mentally ill were placed in asylums and prisons where they received inhumane and insufficient care. Emil Kraepelin was the first to described schizophrenia in 1896. Kraepelin used the term dementia praecox, to characterize a distinct form of dementia marked by poor mental function in addition to reoccurring delusions and hallucinations [Burton, 2012]. In 1911, Eugen Bleuler renamed dementia praecox to schizophrenia (‘schizo’=split; ‘phren’= mind) and further characterized the disorder by noting the incidence of positive and negative symptoms. Within the last century, the neurological basis and associated therapies of schizophrenia have increased. Patients with schizophrenia are no longer subjected to crude forms of therapy as researchers search for long-lasting antipsychotic medications. 

Currently, schizophrenia is understood as a highly heritable and debilitating psychological disorder with a world-wide incidence of approximately 1%. Despite advancements, the cause of schizophrenia is still unknown, and many individuals afflicted with this disorder are unable to live a normal life. Instead, these individuals are dependent on family members and medical professionals. The economic costs associated with the symptoms of schizophrenia total an upwards of $63 billion dollars in the United States alone [Wu et al., 2005]. If the suffering of patients and families is not enough motivation to fund schizophrenia research, the economic burden should be. Patients afflicted by schizophrenia exhibit a variety of positive, negative and cognitive symptoms that vary among individuals. Positive symptoms are characterized by psychotic behaviors not seen in healthy individuals. Such symptoms include, hallucinations, delusions, thought disorders (disorganized thinking, thought blocking, neoglisms) and movement disorders (stereotyped movement, catatonia). Flat affect and lack of pleasure in everyday life are considered negative symptoms because they are qualities that disappear in individuals presented with the disorder. Finally, cognitive symptoms are characterized by a deficits in working memory, executive functioning and attention [NIMH, 2015]. Symptoms of schizophrenia typically manifests during adolescence and early adulthood, between the ages of 16 and 30. Childhood onset of schizophrenia is rare, but, does occur. However, symptoms of schizophrenia do not manifest once middle age is reached. Sexual dimorphism of this disorder, exists as males tend to experience symptoms sooner and more severely than females. Additionally, males are more likely to be diagnosed with schizophrenia while females are more likely to be diagnosed with schizoaffective disorders. 

Though the precise cause of schizophrenia is unknown genetic and environmental factors have been found to play an important role in the incidence of schizophrenia. As previously mentioned, schizophrenia occurs in 1% of the general population. For second-degree relatives of individuals diagnosed with schizophrenia, the genetic risk is greater than 1% and for first-degree relatives, the risk is around 10%. Identical twins have the highest risk of developing schizophrenia if one twin has the disorder (40-65%) [NIMH, 2015]. However, since the risk of identical twins developing schizophrenia is well below 100%, scientists believe there are environmental factors that contribute to greater vulnerability to. 
  

 Alternatively, differences in brain chemistry and structure may play a role in schizophrenia. Schizophrenia is consistently associated with enlarged ventricles, and an overall reduction in brain size especially in the hippocampus, thalamus and frontal lobes [Roberston, et al., 2006]. Additionally, neuroimaging and immunohistochemistry of post-mortem brains of schizophrenic patients were marked by neurological abnormalities, particularly in the hippocampus and neocortex, when compared to normal controls. Imaging revealed neurons in these regions were smaller with abnormal dendritic arborization and synaptic organization. Moreover, immunohistochemistry found a marked decrease in biomarkers for GABAergic inhibitory interneurons [Lewis et al., 2005]. Taken together, this disorder is characterized by a reduction in synaptic organization and connectedness coupled with a decreased expression of GABAergic interneurons. These structural changes are correlated with the deficits in the formation, maintenance and orchestration of synapses that disrupts normal brain function.   

Genetic and Environmental Factors

As previously mentioned, schizophrenia has a strong genetic basis. Familial studies implicate a strong genetic component to the susceptibility of schizophrenia and several candidate genes implicated in schizophrenia as well as comorbid psycho-affective disorders has been identified. Disrupted-in-schzophrenia-1 (DISC1), Neuregulin (NRG1), Nuclear receptor related 1 protein (Nurr1), and Dystrobrevin binding protein 1 (DTNBP1) are a few of the top candidate genes that display positive selection for genes associated with schizophrenia [Kivimae et al., 2011; Goncalves et al., 2015]. However, since the risk of developing schizophrenia decreases as the degree of genetic relatedness decreases, and twins do not have a 100% risk of developing the disorder if one twin is diagnosed, environmental insults have been suggested to exert some degree of influence on the susceptibility to schizophrenia. Therefore, schizophrenia is theorized to be the result of genetic and environmental interactions. Environmental factors such as maternal stress, social isolation, immune activation and pharmacological interference have been found to mimic or exacerbate symptoms of schizophrenia when combined with individuals predisposed with genetic risk factors.
    DISC1, is the most characterized gene implicated in schizophrenia. This gene was originally discovered in a Scottish family with a high prevalence of schizophrenia and psychoaffective disorders including: schizoaffective disorder, bipolar disorder, major depression, adolescent conduct disorder and autism spectrum disorders [Kivimae et al., 2011; Millar et al., 2000]. Dysfunction of this scaffolding protein is characterized by a balanced translocation between chromosomes 1 and 11 that has been linked to the development of psychosis. Additionally, DISC1 interacts with other proteins important to functions of intracellular signaling, neurodevelopment and synaptogenesis [Gamo et al., 2013].  

Evolutionary Perspective of Schizophrenia

  
Human evolution is predominantly characterized by the transition to bipedalism and the evolution of brain size. The evolution of brain size led to increased cognition and executive functioning, in addition to, more complex forms of language. The increase in brain size was marked by increased development of the neocortex, with a significant increase in size and complexity of the prefrontal cortex (PFC). Increases of the PFC led to advantages in emotional processing, motor control, and regulation of behavior in response to environmental stimuli [Goncalves et al., 2015]. One theory suggests genetic changes that caused these enhancements occurred over 50,000 years ago when Homo sapiens transitioned from precursor hominid species [Crow, 2000]. Additionally, these enhancements may have occurred when H. sapiens adapted to live in bigger social groups forced to forage for sustenance. In these conditions, individuals evolved to cooperate, empathize and access the emotional states of other with cognitive adaptations [Isler & Schaik, 2006; De Dreu & Kret, 2015]. In order to perform these energetically demanding tasks, a balance between brain size and energy demand was established. To meet the energetic demands imposed by evolution of brain size, scientists believe species increased energy intake and production or reduced the amount of energy used by other bodily functions.


In order to obtain the energy necessary to maintain basal function, the brain is dependent on oxidative phosphorylation. At rest, the human brain uses approximately 20% of total body oxygen consumption. This can be compared to apes that use 13% and other vertebrate mammals that need 2-8%, but are considered to be less intelligent [Mink et al., 1981]. The amount of total body oxygen consumed only increases when performing energetically demanding tasks. Glucose metabolism is an important source of energy within neuronal mitochondria that are needed for oxidative phosphorylation and intracellular Ca2+ regulation to maintain homeostasis. Moreover, mitochondria that move within neurons are essential for processes that contribute to neurogenesis and neural plasticity including: neuronal differentiation, neurite outgrowth, neurotransmitter package and release, and dendritic modeling [Cheng et al., 2010]. Comparative genomics suggests mitochondrial genes coevolved with increased metabolic processes and neuronal activity. Mitochondria adapted to produce more efficient means of electron transport during oxidative phosphorylation thereby increasing energy levels necessary to maintain brain function. This is thought to have coevolved with increased gene-expression levels of genes associated with energy metabolism and synaptic connectivity in the human neocortex compared to non-human primate relatives [Grossman et al., 2004]. Schizophrenia is thought to be a human specific disease because its clinical symptoms indicate dysfunction among genes and/or pathways involved in human brain evolution [Goncalves et al., 2015]. In particular, changes in metabolic pathways have been implicated in disorders like schizophrenia that impact cognitive abilities. 

Methods & Materials


Animal Models of Schizophrenia


To study schizophrenia, researchers must study the circuitry and molecular mechanisms of human brain. However, because the organ is so vital to human life, obtaining the necessary samples is difficult and impractical. Tissue donated from post-mortem patients have led to several advances in neuroanatomical differences observed in the disorder, but physiological information cannot be obtained from dead tissue. Additionally, studying post-mortem brains does not provide insight needed to determine whether structural changes are a cause of schizophrenia or a result of the disorder. Instead, animal models are used because the brains basic circuitry and molecular mechanisms are conserved among many species throughout evolution [Noriyoshi et al., 2014]. Traditionally, gene mutations identified from patient samples have been isolated and then genetically modified in a mice (Figure 1a). Mice exhibit validity if (1) there is a mutation in the gene that has been supported by human literature, (2) physical or behavioral phenotypes associated with the disorder are displayed, and (3) mice exhibit similar phenotypic response to therapy seen in humans. Despite construct validity, caution must be used when interpreting results because differences between human and rodent brains exist. Therefore, some results may not translate to humans, which may explain why some mouse therapies fail in preliminary stages of clinical trials. 

Comparative Genomics

A second strategy for investigating human evolution of the brain and psychiatric disorders is a hypothesis-generating approach (Figure 1b). Collecting data for comparative genomics, neuroanatomical features and behaviors in human and non-human primates will provide a library of information on the evolution of the human brain. As access to the fossils of archaic humans such as Neanderthals and Denisovans increases, their genome should be sequenced and included in comparative analysis. Behavioral and some neuroanatomical features unique to humans can be analyzed by visually observing physical differences between species. However, next-generation sequencing techniques including, Illumina, RNA-seq, chromatin immunoprecipitation coupled DNA sequencing (ChIP-seq) and de novo genome assembly can be used to identify specific genes and mutations unique to human evolution. Genomic sequences can be added to and/or downloaded from the genome-wide association study (GWAS) to examine SNPs from schizophrenia meta-analysis. GWAS allows for the comparison highly conserved sequences within and across species as well as an indication of genetic expression levels. Once identified, the behavior of human cells and “humanized animals” can be analyzed and modified in order to target and develop novel treatments for schizophrenia. 

Results


Gene-environment animal models of schizophrenia


Animal models have led to novel discoveries in the pathophysiology and potential therapeutic targets of schizophrenia. Transgenic DISC1 rodent models have been created that express phenotypic symptoms of schizophrenia seen in humans. DISC1 mice exhibit negative symptoms including depression (as measured by increased immobility in forced swim tests, as well as, tail suspension tests) and anxiety (measured by reductions in time spent in the open arms of elevated plus mazes) [Gomez-Sintes et al., 2014; Kivimae et al., 2011]. Pre-pulse inhibition and startle assays measured cognitive deficits in sensorimotor gating and deficits in spatial and working memory were exhibited by delayed matching to position/non-matching to position tasks [Gomez-Sintes et al., 2014; Li et al., 2007; Kvajo et al., 2008]. Finally, positive symptoms were noted by the hyperactive ambulation of males in the open field assay [Gomez-Sintes et al., 2014]. Phenotypes presented by DISC1 mutant mice were highly dependent on the strain of mice used, translocation site of the mutation and the sex of the animal. 


Immunohistochemistry of brains from post-mortem schizophrenic patients has indicated a reduction in biomarkers, parvalbumin (PV) in GABAergic inhibitory neurons in regions of the hippocampus, anterior cingulate cortex, and the PFC (Figure 2a) [Brisch et al., 2015; Ibi et al., 2011; Lewis et al., 2005]. Other GABAergic interneuron biomarkers, like calretinin (CR) exhibit similar expression levels in schizophrenic and control humans and animals (Figure 2b). This is significant because though comprising roughly 15% of neurons in the cortex, PV GABAergic interneurons serve an essential role in the maintenance and orchestration of normal brain function. The maturation process of these neurons is not well understood, but accumulating evidence suggests N-methyl-D-aspartate receptor (NMDAR) signaling influences the maturation of GABAergic interneurons.


    Environmental stress was also found to influence the pathogenesis of mental disorders by disrupting the homeostatic physiological stress response modulated by the hypothalamic-pituitary-adrenal (HPA) axis to increase production of glucocorticoids [Cash-Padgett & Jaaro-Peled, 2013]. The increase in glucocorticoid levels leads to increased sensitivity to stress as well as deficits in brain maturation. Due to this, individuals in stressful environments are prone to the development of a variety of mental disorders including schizophrenia and depression. Previous studies have examined environmental insults of psychological, immune and pharmacological stressors in the form of maternal separation, social isolation, social defeat, viral infections and drug abuse. Restraint stress was shown to impair working memory in rodents [Gamo et al., 2013]. The stress of social isolation has been linked to deficits in sensorimotor gating, changes in the projections of dopaminergic neurons, as well as, increases in despair and locomotor activity [Niwa et al., 2010].  Finally, mice injected with viral constructs that induce innate immune responses, showed deficits in short-term memory, object recognition, context-dependent learning, social interaction and immunoreactivity of parvalbumin interneurons in the prefrontal cortex [Ibi et al., 2010].  

    Independently both genetics and the environment can increase susceptibility to psychiatric disorders like schizophrenia. However, those with the greatest risk of being diagnosed with schizophrenia are individuals with a genetic and/or environmental insults during prenatal development and adolescence. Animal models showed that when combined with genetically predisposed DISC1 mice, animals faced with environmental stressors during adolescence exhibited greater deficits in executive functioning (Figure 3a), working memory (Figure 3b) and increased movement disorders (Figure 3c) compared to wild-type, or DISC1/no stress cohorts. Epigenetic experiments lend support to the ‘two-hit’ model of schizophrenia pathogenesis.  The first ‘hit’ occurs during the perinatal period when the embryo is exposed to genetic or environmental insults, which makes children more vulnerable to psychiatric disorders. Prenatal exogenous and endogenous environmental factors part of the ‘first hit’ include: maternal malnutrition, repeated psychological stress, exposure to infection, obstetric complications, gut microbiota and changes in prenatal endocrine function. These factors along with schizophrenia candidate genes primes the brain for neuropathological disorders by increasing neuroinflammation, degenerating axons, myelin and oligodendrocytes in addition to altering brain connectivity and morphology [Robertson et al., 2006; Debnath et. al., 2015]. During adolescence, a second round of environmental insults (exposure to stress, drugs, trauma and infection) unmasks the endophenotypic traits associated with schizophrenia by activating the inflammatory, oxidative and nitrosative stress pathways, mitochondrial dysfunction, apoptosis and progressive brain changes. Together, the impacts from these two hits synergistically combine to manifest symptoms of schizophrenia in adulthood. 

Coevolution of schizophrenia with the evolution of increased brain size and complexity not a human specific trait


Humans, ten species of non-human primates, thirty-one non-primate eutherian mammals, two marsupials and one monotreme were used for the identification of schizophrenia related orthologues. Of the forty-two eutherian mammals, two marsupial and one monotreme genomes analyzed from the gene-disease associations compared by the Genetic Associated Database (GAD), several orthologues associated with psychiatric disorders were found [Ogawa & Vallender, 2014]. Orthologues were found for schizophrenia genes, as well as, genes associated with autism, ADHD, bipolar disorder, depression, anxiety, addiction, eating disorders, Alzheimer’s, Parkinson’s, migraine and stroke. GAD revealed positive selection (as measured by dN/dS mutation rates) of genes associated with schizophrenia. Both human and non-human primates (particularly catarrhines) showed similar ratios of positive selection. Interestingly, when compared to other large brained mammals, cetaceans like the bottle-nosed dolphins and killer whales, showed higher average dN/dS ratios for psychiatric disorder orthologues (Figure 4). Taken together, this data suggests genes associated with schizophrenia are not uniquely human; rather these genes were seen in closely related apes, old world monkeys and some toothed cetaceans. This information is not particularly surprising since compared to other mammals considering anthropoid primates and odontocete cetaceans show similar evolution rates to humans. Primates and cetaceans shown a greater brain to body mass ratio and greater variations in encephalization quotients indicating a relaxation of evolutionary constrains [Boddy et al, 2012]. Furthermore, of the 228 genes discovered to be under positive selection in dolphins, twenty-seven were found to be associated with processes of the nervous system including synaptic plasticity, human intellectual disorders and sleep [McGowen et al., 2012]. Additionally, increased selection was found on genes related to mitochondria expression and metabolism.


An increase in brain mass must be compensated by an increase in energetic demands. Increased energy may come from an increase in metabolic turnover rate, neuronal mitochondria, reallocation of energy from other functions or a combination of events. A positive correlation between brain mass and basal metabolic rates among primates indicates some species do compensate for larger brains by increasing metabolic turnover rates [Isler & Schaik, 2006]. When energetic demands are not met, deficits occur in working memory, executive functioning and language and an increase in psychosis is observed (Figure 13). Humans with schizophrenia display abnormalities in glucose tolerance and increased insulin resistance. Since glucose in the brain is metabolized in the brain, abnormalities in glucose metabolism suggests schizophrenia may be associated with mitochondrial dysfunction [Goncalves et al., 2015]. Additional support stems from lower metabolic rates and lower blood flow in the frontal brain during cognitive tasks, altered levels of glycolic enzymes and byproducts in the brain, reduced number of mitochondria in the striatum and hypoplastic mitochondria in oligodendrocytes in the caudate nucleus and PFC of schizophrenic individuals compared to healthy controls. From these results, it becomes clear how mitochondrial dysfunction can lead to deficits in neurotransmission and synaptic plasticity which increases the susceptibility to biological (oxidative) and environmental stress. 


Discussion

    Historically, individuals suffering from schizophrenia and other psychiatric disorders were stigmatized, dehumanized and shunned by the general population. Fortunately, the way society viewed schizophrenia has evolved. With this change in perspective came novel concepts and methods to identify the neuroanatomical, behavioral and physiological disruptions associated with schizophrenia. Though the root of schizophrenia has not been found, use of patient samples, animal models and comparative genetics has led to many advancements in genes and pathways involved in the disorder. Future research must continue to have a holistic approach while investigating the pathogenesis of schizophrenia due to its polytypic nature. One theory of the development of schizophrenia if the two-hit model. Environmental or genetic insults during natal development can prime the brain to become more vulnerable to psychosis. Furthermore the risk of pathogenesis increases exponentially if individuals that have been primed during development are exposed to environmental stressors during adolescence. If so, that individual is likely to manifest symptoms associated with schizophrenia in adulthood. A second, more evolutionary theory for the pathogenesis of schizophrenia is related to the mitochondrial dysfunction in the brain. Essentially, if mitochondria are not meeting the energy demands associated with increased cognition in the human brain, individuals are prone to psychiatric disorders like schizophrenia.  However, moving forward, one area of focus should be on characterizing the influence of AMPA and NMDA receptors at the molecular level and in the context evolution due to their direct influence on learning and memory. ***


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