The term “schizophrenia” that in Latin means shattered or broken brain was first coined as “Démence précoce” by the French psychiatrist, Bénédict Morel and later by Emil Kraeplin in 1893 who popularized by the term “dementia Praecox”, distincted it from mood disorders for having a more severe and broad psychopathology with an onset after puberty. But it was not until Kurt Schneider, in early 20th century, differentiated “schizophrenia” from other psychotic disorders, by introducing “first rank” symptoms, e.g. delusions and hallucinations that schizophrenia as we know it today. The concept of the disease as a “neuro-degenerative” condition that started with “dementia Praecox” or premature dementia continued until in 1980’s when the concept of the disorder as “neuro-developmental” condition was raised. Although to this very day, there are still confusion and controversies over the two concepts of degeneration vs. developmental, the neuro-developmental theory of schizophrenia is predominant in the field.
The Link between Infections and Schizophrenia
The first suspicion of a link between schizophrenia and infection rose as early as 1950, by Abaskuliev, a Russian psychiatrist and a decade and half later again by another Russian psychiatrist, Mironov, in 1964 who added the concept of “neuro-developmental” nature of the disease to its “infective psychopathology”! in the western hemisphere, only in 1970’s , Lord and colleagues were perhaps the first to report recovery of a strain of adenovirus type 7 from the cultured brain cells of deceased 71 years chronic schizophrenic. These frontiers concluded that their discovery “may indicate the reactivation of a latent infection” with one of the few adenoviruses that had been associated with clinical encephalitis. Soon the idea of latent infection in the pathophysiology of schizophrenia was adopted by many others and extended globally among surprised researchers including in US, where among others, Torrey and colleagues in 1977, on the basis of the high rate of infections in spring and winter months and the influenza epidemics of 1920’s and 1950’s, raised the idea of seasonality of schizophrenic births. Hereby the infective concept of schizophrenia widespread across the globe and covered many infective agents from viral to bacterial and even parasitic, e.g. Influenza virus; Cytomegalovirus; toxoplasmosis; HSV 1 & 2; Borna virus; Coxakievirus; bacterial infections such as streptococaal; Chlamydia; parasitic infections, e.g. Toxoplasma gondii, etc.
The relatively strong observation of the association between infection and schizophrenia, convinced some authorities to perceive this disorder as an “autoimmune disease”. The low inheritance rate of schizophrenia, including the concordance rates for monozygotic twins (36-58%) falling short of 100%, further supported the theory of infectious origin of schizophrenia and its autoimmune pathophysiology. While some researchers continued to search for the trace of infections in the patients with schizophrenia, soon it became apparent that the transmission is not horizontal and not directly in the individual patients, to look for example for antibodies in the CSFs, sera and even post-mortem brains of the patients, but vertically, i.e. the infections have been gestational and in pregnant mothers who gave birth to schizophrenic off springs.
Among all the viral and microbial search for identification of an infectious causal link to schizophrenia, the role of retroviruses is outstanding. have been the suspicious cause of schizophrenia. Retroviruses, the single-stranded RNA viruses possess unique feature that once inside the host cells cytoplasm, they use their own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus called retro (backwards). This new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, translating and transcribing the viral genes along with the cell’s own genes, producing the proteins required to assemble new copies of the virus. It is difficult to detect the virus until it has infected the host, which at that point, the infection will persist indefinitely. In fact studies of retroviruses have led to the first demonstrated synthesis of DNA from RNA templates, a fundamental mode for transferring genetic material that occurs in both eukaryocytes and prokaryocytes, the frontiers of life on earth. It has been speculated that the RNA to DNA transcription processes used by retroviruses may have first caused the more chemically stable DNA to be used as genetic material.
When retroviruses have integrated their own genome into the germ line, their genome is passed on to the following generation. . Many endogenous retroviruses play important roles in host biology, such as control of gene transcription, cell fusion during placental development in the course of the germination of an embryo, and resistance to exogenous retroviral infection. While exogenous retroviruses have been already linked to the autoimmune disorders such as Multiple Sclerosis, the endogenous retroviruses could be the causes of many genetic diseases such as schizophrenia as they have become part of our genome. Schizophrenia that has been hypothesized as a neuro-developmental disruption during fetal growth, has been hypothesized to be caused by endogenous retroviruses that are known for cell fusion during placental development in the course of the germination of an embryo.
Schizophrenia as an “immune” or “autoimmune disorder
With the advent of more sophisticated immunological methods of detection of viral invasion, the new 21st century evidenced reports of appearance of different “cytokines”, and other inflammatory processes, in the prenatal serum of schizophrenic samples as strong fingerprints of prenatal exposures to viral infections. This has been based on the fact that most bacteria and viruses do not cross the placenta; but their damaging impact to the fetus could be detected through the maternal antiviral responses to infection (e.g. proinflammatory cytokines). Maternal exposure to infection alters pro-inflammatory cytokine levels in the fetal environment, which may have a significant impact on the developing brain. The mothers of schizophrenic subjects have been shown to have higher second-trimester IL-8 (another cytokine or inflammation or autoimmune finger prints) serum levels than those of the mothers of comparison subjects. But since not all inflammatory or autoimmune factors are higher, nor not any gestational infections in the mothers leads to the causation of schizophrenia in the off springs, it has been hypothesized that there maybe some genetic susceptibility perhaps in the form of functional polymorphisms in some of the inflammatory or autoimmune markers such as the Interleukines or cytokines.
Infection, genetic and immune systems interactions:
Therefore it seems that there is an interaction between maternal gestational infection, genetic susceptibilities, and neurodevelopmental process of schizophrenia during a sensitive time window, e.g. second trimester. Histocompatibility Leukocyte Antigens (HLA-G) as an autoimmune protection against any uterine invasions, e.g. by infections could have been disrupted so failing to maintain such inhibitory potential to down regulate the detrimental inflammatory cytokines, thus rising to the neurodevelopment of schizophrenia. In support of such hypothesis, it has been shown that structural brain alterations following fetal exposure to the inflammatory cytokine interleukin-8, fitting the neuroanatomical template characteristic of schizophrenia, e.g. significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex, right posterior cingulate, right caudate, bilateral putamen and the right superior temporal gyrus volumes. While the cytokines and HLA consolidated the infectious theory of schizophrenia, the Major Histocompatibility Complex (MHC), another major inflammatory and autoimmune marker, and their gentic loci have been in support of the neuro-developmental concept of this disorder. MHC that are expressed on neurons in the central nervous system throughout development and into adulthood, regulate many aspects of brain development, including neurite outgrowth, synapse formation and function, long-term and homeostatic plasticity, and activity-dependent synaptic refinement.
Symptoms and course of illness worsening shortly after the onset of the illness that have been taken by many over centuries and still by some experts, as signs of neuro-degeneration in schizophrenia in contrast with its neurodevelopmental process, apoptosis, or programmed cell death, especially synaptic apoptosis in which apoptosis is localized to distal neurites without inducing immediate neuronal death, has been the right explanation. This apopotosis is short-lived for about a few years after the onset of the illness, so is not long-term, chronic and does not involve DNA fragmentation as in case of classic neurodegenerative disorders. The disruption in the neuroplasticity or neur-connectivity of the brain as one of the most recent pathophysiologic framework of schizophrenia fits well into the neuro-inflammatory and neurodevelopmental model of the illness.
From infection to Schizophrenia: The pathophysiology of an insult
First: The Prenatal Insult and Maternal/Fetal Immune Reactions
As detailed above, there is almost no doubt in the fact that schizophrenia is a byproduct of aberrant brain development at a very sensitive time window that seems to be long before the first clinical onset. With strong evidence, this time window seems to be prenatal, through a maternal insult to the fetus that is most probably of infectious origin. The infectious hypothesis of schizophrenia that complements the neuro-developmental theory of the disease, fits some seasonal births of the disease, the genetic concordance rate of the disease that is only 40-50% between identical twins, who share 100% the same genetic pool. The bigger question and dilemma now is how an infection, which is not yet clear to be specific or non-specific, would trigger the pathophysiologic machinery of schizophrenia. What we know through years of observation and research is that such prenatal infection(s) in the mother at a very sensitive time window, invade(s) the fetal brain and trigger(s) a series of immunological reactions that altogether disrupts the normal fetal brain development and years after birth, predominantly during adolescence years, leads to the manifestation of schizophrenia. As genetic susceptibility alone is not sufficient to cause schizophrenia per genetic linkage, genome wide association studies (GWAS), etc., nor the infection alone as no prenatal infection(s) have shown to cause the disease in the off-springs of all affected mothers. Therefore it seems that an interaction of infectious insult at a specific window time of brain development in genetically vulnerable fetuses could produce schizophrenia. In support of such theory, the Maternal Immune Activation (MIA) model of schizophrenia in pregnant lab rodents and even recently in primates, by administration of viral particles and infecting proteins have shown behavioral, neurochemical, psychophysiologic, and histologic abnormalities found in patients with schizophrenia. Of neuro-chemical relevance to the dopaminergic hypothesis of schizophrenia, administration of poly I:C to pregnant rodents has been shown to cause an increase in the number of mesencephalic dopamine neurons in the fetal brain during mid to late gestation, accompanied by changes in fetal expression of several genes involved in dopamine neuron development.
Second: The Sensitive Time window
From about 15 weeks of gestation, the axons and dendrites start to outgrow to form the highways of the brain for connection and communication that continues until about 18 months of life. Around the same time synapses, that are the crossroads of neurons are formed for inter-neuron communication. This happens almost at the same time that myelination, essential for conducting signals and impulses, and vital for regeneration of the whole nervous system (the only body organ to regenerate after insults) that continues until mid-adolescence. During normal development, critical periods occur in a predictable temporal sequence, as depicted with examples of vision, language, and higher cognitive function. Following an insult such as infection, certain critical periods may be developmentally delayed or halted. Critical periods might then become incorrectly synchronized or uncoupled from one another across the brain. Alternatively, the extended duration of one critical period may stall the onset of others.
The survival and growth of neurons is regulated by survival factors, called trophic or nerve growth factors (NGF), discovered by Stanley Cohen and Rita Levi Montalcini who won the Nobel Prize in Medicine in 1986. There are several NGF’s including the most influential ones, BDNF (Brain Derived Neurotrophic Factor) and GDNF (Glial derived neurotrophic factor). BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. The neurotrophic factors in the brain, is active in the hippocampus, cortex, and basal forebrain, areas vital to learning, memory, and higher thinking. GDNF is a potent trophic factor for striatal neurons, hence the survival and differentiation of dopaminergic neurons. A microbial insult after 15 weeks of gestation, could disrupt the above-mentioned neuro-developmental processes. Moreover the neuro-receptors would also be affected later on in life as there are age-related differential binding potentials. For example, among different dopamine (DA) receptors, D1 receptor that is the most abundant of the DA receptor subtypes normally decline in binding potential by age, most prominently in cortical regions including the dorsolateral prefrontal cortex. Also expression of the dopamine D2 receptors in the prefrontal cortex normally peak in infancy then decline and by adolescence reach the adult levels. All these after an insult could be disrupted and there would be no normal decline in the number and potential binding of D1 and D2 receptors, supported by dopaminergic theory of schizophrenia.
Furthermore, GABA, the chief inhibitory neurotransmitter in a mature brain, acts primarily excitatory and appears earlier than glutamergic transmission in the developing brain. In the developmental stages preceding the formation of synaptic contacts, GABA regulates the proliferation of neural progenitor cells, the migration and differentiation, and the formation of synapses, via BDNF expression, and also regulates the growth of embryonic and neural stem cells. An early insult to the fetal brain development could disrupt normal developmental process of conversion of GABA neurotransmission from excitatory to inhibitory. This could also delay or disrupt the glutamate neurotransmission that normally develops later on and is vital for the modulation of synaptic plasticity. Moreover exposure to an insult such as infection in the developing brain could trigger excitotoxicity in the brain through excessive glutamergic reaction and cause neuro-degeneration.
At the neuroanatomical level, the pronounced increase in total cortical grey matter volume, occurs from 29 weeks to 41 weeks of gestation with a double increase from 20% to 40%, along with a marked increase in the cerebral gyration. In contrast to the marked changes in cortical grey matter volume, subcortical regions including basal ganglia and thalamus show no significant volume changes during the observed period of brain development. The increase in the cortical grey matter volume that relates primarily to neuronal differentiation, dendritic and axonal branching and gyral development rather than to an increase in numbers of neurons, is complete by approximately 20-24 weeks of gestation. Therefore an early insult such as infection to the fetal brain development could disrupt all the above neuro-developmental processes. Moreover, the process of myelination of brain white matter that occurs principally from 29 to 41 weeks of gestation could be disrupted by the microbial insult. That is why neuroimaging studies in schizophrenia have revealed global differences, suggesting the impairment of multiple brain circuits, with some brain regions showing focal abnormalities, altered structural integrity of white matter in frontal and temporal brain regions and tracts such as the cingulum bundles, uncinate fasciculi, internal capsules and corpus callosum. In summary it is during a sensitive time window, perhaps the second trimester, that an insult such as prenatal maternal infection could cause major disruption in the major cortical grey matter circuits, the integrity of white matter pathways, neuronal differentiation, dendritic and axonal branching, gyral development and neuro-plasticity, is in the second trimester.
Third: The Genetic Vulnerabilities
Thus far prenatal maternal infection at a sensitive time window of fetal brain development could cause a non-specific neuro-developmental pathology later on in life. Perhaps for the damage to be specific and causing an illness such as schizophrenia, there should be some specific genetic vulnerability. But genetic studies including the modern genome wide association studies, have failed to identify any specific gene(s) in schizophrenia. Moreover the concordance rate of the disease in identical twins is not more than %50 that is almost the same rate as the off-spring of both parents affected. Only in sporadic cases, a number of replications of larger genetic structural variants or genetic mutations, such as CNVs (Copy Number Variants), and smaller genetic mutations e.g. SNP’s (Single Nucleotide Polymorphisms) have been conclusive. These genetic mutations occur across many different chromosomal regions, encompass a number of different genes, and usually have high but incomplete penetrance. In these cases, most of the identified CNVs and SNP’s are de novo and not inherited. These different chromosomal regions with rare CNVs and SNP’s capable of causing schizophrenia, usually do so one at the time! Therefore it seems that genes alone, one or more could not cause schizophrenia alone, and genetics cannot explain the etiopathology of this disorder. That is why schizophrenia genetics needs epigenetics, where the genetic and environmental factors interaction are both counted in the pathophysiology of the disorder.
Genetic mutations could be de novo or primary through errors in DNA methylation programming, or secondary caused by environmental insults such as infecting agents or “epigenetic misregulation” of the genome. As it was discussed earlier, epigenetic misregulations, e.g. sporadic CNV’s or SNP’s occur in schizophrenia even without genetic liability, and most probably by environmental pathogens. Whatever the origin, epigenetic markings of DNA are heritable and transmitted through mitosis in somatic cells during morphogenesis and growth. As most infecting agents such as viruses do not cross the placenta, the pathological mechanism to the fetus, as presented earlier, is indirect and through maternal immune responses, e.g. proinflammatory cytokines such as interleukin-6, -8 that have been experimentally shown to increases the risk of schizophrenia. More recently there have been experimental animal studies in support of epigenetic mutation of human genes by microbial invasion and leading to diseases with several years in latency such as in the case of schizophrenia.
The Final Step: The Beginning is the End
For long it was thought that the onset of schizophrenia is when the psychotic symptoms appear. Later on a prodromal stage before the onset of psychotic symptoms, by observation of odd and bizarre changes in the personality and behaviors of the yet to be patient was appreciated. But the neuro-developmental concept of schizophrenia not only changed the old Kreaplinian concept of the disease as a neuro-degenerative one, but revealed the fact under the tip of the iceberg that the disorder has had a long-term pathological process, before the first clinical manifestation. Therefore as I have presented here, the clinical onset of the disease which seemed to be the beginning, it is in fact the end of such underlying pathophysiological process that initiated almost two decades in the mother before the birth of the victim patient, as a prenatal maternal infection. The differentiation between the developmental processes of different neurodevelopmental disorders, e.g. early onset in case of autistic disorders and later onset in case of schizophrenia has been explained as “the induction of persistent inflammation may be more relevant for the etiopathogenesis of autism by contributing to phenotypic abnormalities specifically seen in this disorder. By contrast, latent immune inflammation may be essential to the pathogenesis of schizophrenia-specific brain and behavioral abnormalities.” In support of this hypothesis, there are several lines of evidence that autism but not schizophrenia is characterized by relatively severe chronic inflammation, both in the periphery and in the CNS, e.g. a nearly 50-fold increase in TNF-α level in the cerebrospinal fluid (CSF) of autistic children, and severe inflammation in the brains of autistic patients, characterized by prominent activation of microglia and astroglia cells and enhanced pro-inflammatory cytokine and chemokine expression in multiple brain areas, including the cerebellum, cortex, and white matter tracts.
Another important differentiation is that prenatal exposure to relatively severe forms of maternal immune challenge, i.e., following chronic or sub-chronic maternal infection/inflammation could cause latent impact, while by contrast, acute prenatal inflammation (e.g., by single PolyI:C administration) appears to be largely devoid of long-term neuroinflammatory effects in the adolescent or adult offsprings. In contrast to autism, chronic neuroinflammation seems less prominent in schizophrenia. Indeed, even though peripheral pro-inflammatory markers such as IL-6 appear to be elevated in at least a subgroup of schizophrenic patients, the reported increases are relatively modest. Furthermore, despite considerable research efforts, imaging and post-mortem immunohistochemical studies provide very little evidence for over-activation of microglia and astrocytes in the brains of schizophrenic patients.
Another line of evidence for the latent onset or clinical manifestation of schizophrenia is in the stages of brain development, specially higher cortical functions that matures only after the onset of adolescence, the time of maturation and development of all the brain’s plasticity, connectivity, etc. Schizophrenia as a psychotic illness, or a disorder of the human’s logic, reality touch, higher level of salience and coherence in all emotional, linguistic and logical levels that require maturity, occuring from adolescence into adulthood. Experimental models in support of this have shown that prepubertal humans rarely develop psychosis after exposure to NMDAR antagonists, such as PCP or ketamine. NMDAR-hypo state that was created prenatally can remain quiescent throughout childhood until maturational changes in brain circuitry make the brain function more vulnerable to the underlying biological defects which creates the stage for schizophrenia symptoms to emerge. Moreover it has been recently shown that progression from prodromal symptoms to manifest schizophrenia could be significantly reduced with neuroprotective compounds, such as long chain omega 3 fatty acids.
- Psychiatry has come a long way to recognize schizophrenia as a neuro-developmental disorder. But this conviction still remains mostly in the scientific arena and has not yet been fully revealed at a large scale for practicing psychiatrists and others caring for the schizophrenics. This revelation is vital and holds the future direction of early diagnosis, treatment and prevention. Schizophrenia is no longer a static disease to be recognized and treated when it happens, but it is a disease in the process years before the first clinical onset, even the prodromal stage, from the time of fetal development. The discovery of the neurodevelopmental basis of schizophrenia paves the way for such recognition in other neurodevelopmental disorders such autism spectrum disorders. These disorders while sharing some clinical features at the surface and some underlying pathophysiology with schizophrenia, at the same time, there have major differences both at the clinical surface, and underlying pathophysiological mechanisms, that leads us to the second main conclusion.
- The neurodevelopmental basis of schizophrenia is a process that needs causation, which over the past 65 years, has widely been accepted to be of infectious origin. The evidence for the prenatal maternal infection triggering maternal and fetal inflammatory immune reactions, are so strong and sensible, fitting the developmental time window and the neurobiological damages ending in schizophrenia, latently years later that other suspected etiologies, e.g. obstetric complications and postnatal environmental factors such as stress seems to be unfit and out of question. Although the infecting agents could be non-specific and of bacterial or viral origins, the immunological inflammatory reactions, e.g. secretions of cytokines in defense could be the direct damaging factors. The severity, chronicity and latency of the infections as discussed are other determining factors in causing schizophrenia or other neurodevelopmental disorders.
- To the disappointment of the genetic research enthusiasts and their laborious efforts over decades, genetics seems not to have any specific and direct impact in the etiology of schizophrenia. Therefore it appears that no single or combination of genes could cause schizophrenia directly, as there is no strong evidence of any specific gene(s), but sporadic CNV’s and SNP’s as discussed here and could easily be caused by the microbial invasions. These sporadic CNV’s and SNP’s or epigenetic mutations, later on even in the absence of another prenatal infection could be passed on to the next generations through inheritance, i.e. familial schizophrenia. SNP’s that accounts for about 1% of human genomic variation (in contrast with 13% of CNV’s) and affect one single nucleotide base (in contrast with CNV’s, affecting large regions of genome) have been subject of studies in schizophrenia as in other complex diseases.
Yesterday, Today and Tomorrow
The history of psychiatry, or schizophrenia does not end today! The history goes on and our today’s conviction will be a belief of the past. We can only learn from the past for today and the future, and unfortunately this learning is not achieved easily due to dogma and resistance for change. For thousand years, we as humans thought of the mental illness and at the top, schizophrenia as insanity and we isolated the patients into asylums and in chains or executed them under the name of God for witchcraft and demonic possession! Then after the scientific revolution and great advancement in medicine, we understood schizophrenia wrongly as a static neuro-degenerative disease and stubbornly pushed the old idea for more than a century, despite the strong scientific evidence to the contrary! Now at the present time, while hoping that the past is gone and the rigidity is done with, after our major achievement in the human genome project and mapping all our genes, try to prove by our genetic studies that genetics is everything and we can soon discover the genes for all the human diseases! We forget the simple fact that genes, simply are biological templates, where we actually can find the fingerprints of the environment and is not the causation of anything per se. Even our simple Mendelian traits such as the color of our skin, hair and eyes are affected by the environment. This has already taken us to the present time or today to recognize the importance of the impact of environment on us or our genetic make up or template, i.e. “epigenetics”. We have come a long way not to look for a simple chromosomal defects in complex disorders such as schizophrenia, or even a single gene, but to identify pieces of gene mutations through CNV’s and SNP’s as the true underlying genetic process of not just pathology, but natural selection and evolution. We have also appreciate that schizophrenia is heterogeneous, though somewhat narrowly within a diagnostic and symptomatic frame, with marginally different underlying pathophysiology and genetic structure, i.e. with different CNV’s and SNP’s even among the same families. This hopefully will take us from the mentality of the past and today to the future, to truly and deeply recognize the environmental influences or fingerprints on our existence! While we cannot find any gene(s) for schizophrenia or other complex diseases, with our current discovery of CNV’s and SNP’s and more of the kind in the future, we can identify the fingerprints of different environmental impact such as infections on our genome or biological system that has caused us different diseases. In the future hopefully we will be able to root any disorder such as schizophrenia, even its subtypes in a top-down fashion from intermediate phenotypes to their genetic fingerprints through CNV’s and SNP’s, etc. back to the environmental causes, e.g. microbial invasions, even their subtypes!