2. Causes of Schizophrenia

Schizophrenia brain
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dopamine levels and cortical thickness of grey matter are both compromised in patients with Schizophrenia [12]

Schizophrenia falls under the category of psychotic syndromes and is known to be associated with the following symptoms: hallucinations and delusions, motivational impairment, depression, mania and cognitive impairment.[1] Schizophrenia is believed to be the outcome of a complex interaction between susceptibility genes and the environment. Individuals with a family history of schizophrenia are more likely to develop it than someone whose family is unaffected, which likely indicates a genetic component to schizophrenia. But those genes might not be expressed unless they are triggered by stress factors introduced by the individual’s environment.[1] Susceptibility genes that likely give rise to schizophrenia are those that impact prefrontal function including the COMT gene and NRG 1 gene.[2] Stress factors that can trigger schizophrenia in genetically predisposed people include cannabis abuse, an urban upbringing, developmental and prenatal trauma. [1]

Genetic

Genes associated with Schizophrenia
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COMT, NRG 1 and other gene deletions thought to contribute to Schizophrenia [15]

COMT Val

Dopamine levels in cortex and thickness of grey matter in the cortex can both be controlled through the enzyme releasing polymorphic gene COMT. COMT Val allele was found in higher proportions in schizophrenia patients and their siblings than in the control group, and is thought to be associated with cortical thinning in susceptible individuals. [6] COMT enzymes regulate the dopamine release mechanism in the frontal cortex, a process crucial for working memory and attention, both areas lacking in individuals with a higher proportion of the COMT Val allele as opposed to the Met allele also observed in schizophrenia patients. [8] They it is interesting that patients with schizophrenia are not only unable to relate to interpersonal dilemmas, but also don’t have enough of an attention span to observe one in the first place which can be associated with the lower levels of dopamine released which are regulated by dysfunctional COMT Val gene. [8] The deleted region identified for the gene appears to 22q11, which on its own appears be a risk factor for schizophrenia. [9] Additionally it was found that individuals with schizophrenia are homozygous are for the COMT Val allele while individuals without schizophrenia are homozygous for the COMT Met allele in most cases. [9]

NRG 1

Excessive signaling of NRG 1 is thought to be associated with the reduced function of NMDA receptors observed in patients with schizophrenia. The mechanism behind this is NRG1-ErbB signaling pathway suppressed the enhancement of NMDA receptors at the synapse, by interfering with induction of long term potentiation at CA1 synapses and suppressing it resulting in suppressed enhancement of NMDA receptors activation. [7] In patients with Schizophrenia, signaling of NRG1 to ErbB4 pathway inhibits the enzyme Src Kinase which in turn is responsible for the enhancement of NMDA receptor. [7] Blocking Src kinase in the CA1 neurons leads to the failure to induce long term potentiation in the hippocampus. [7] NRG 1 and ErbB signaling pathway is essential in normal development, but it does not stop there as they play a role in adult synptic plasticity. [10] Since it appears this pathway is damaged or disconnected in patients with schizophrenia, it negatively affects processes of learning and memory. [10] ErbB4 receptors are also present in the GABA interneurons, and are responsible for firing of pyramidal neurons in the hippocampus and the cerebral cortex, and appear to be regulated by the same NRG 1 and ErbB signaling pathway, therefore when the path is damaged upstream it relates to deregulation of the interneurons and in turn synaptic plasticity. [10]

How the two interact

A recent paper is a good example for the interaction of the two well studied susceptibility genes COMT Val and NRG 1 that impact prefrontal function and are likely to give rise to schizophrenia. [2] NRG 1 is proposed to be a gene affecting the polymorphic gene COMT Val/ Met, through the NRG 1 signaling pathway and COMT enzymes regulated AKT 1 function. AKT 1 phosphorylation and translocation to plasma membrane by NRG 1 was impaired in Val vs Met carriers of the COMT gene. This paper might have significant findings to our understanding of the pathogenesis of schizophrenia. [2]
NRG 1 promotes adhesion and migration of B lymphoblast cells in the ErbB signaling pathway, however in patients with schizophrenia Migration of B lymphoblasts has been shown to be impaired. [3] The second gene regulating this process is the COMT Met/ Val gene, and it regulates the enzyme activity responsible for B Lymphoblast adhesion and migration in the ErbB signalling pathway. [4] Their most recent hypothesis, is that since NRG 1 regulation is AKT1 dependent, COMT also interacts with AKT 1 to produce the impaired function of this pathway observed in Schizophrenia patients. [2]

Genes and Environment interaction
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There are sensitive periods for specific genes when they can interact with the environment [14]

Environmental

Cannabis abuse

Cannabis has been consistently observed in studies of psychotic syndrome, and in particular the main psychoactive component delta- 9 tetrahydrocannabinol has been observed to cause temporary psychotic symptoms including cognitive impairment in even healthy individuals and an even worse response in individuals genetically prone. [1] The association is not only between Cannabis being the trigger cause for schizophrenia, but also between using cannabis for self medicating when initial symptoms of psychosis appear. [1] There is an association between the COMT Val gene, which is susceptible to Schizophrenia, and an increased abuse of cannabis, with the onset of schizophrenia later in life. [11] Individuals homozygous for COMT Val had the greatest risk, next were individuals heterozygous and individuals at lowest risk were COMT Met homozygous. [11]

Urban upbringing

This broad topic seems initially ambiguous and is harder to study directly, but the general idea is that growing up in an urban area where you are exposed to the risk of deviating from the norm can trigger schizophrenia in certain people. [1] This could be a collective explanation for being a part of a minority group, being exposed to more different types of drug abuse etc. More specifically, there is an association between family context, residential instability growing up and feeling like an outsider in normal social context, which in turn can be the trigger for individuals susceptible to psychotic syndromes. [5]

Developmental and prenatal trauma

Prenatal trauma leading to psychotic syndrome later in life can be induced by factors such as stress levels and nutritional deficiency of mother, specific viral and bacterial infections to name a few. [1]

Since so many common factors contribute to acquiring psychotic syndrome or schizophrenia later in life, why isn’t its occurrence higher? Well, there are subgroups of populations significantly more genetically susceptible to developing schizophrenia triggered by a fairly common developmental factor that might have no effect on someone else. [1]

Bibliography
1. Van Os et al. (2010). The Environment and Schizophrenia. Nature, 468, 203-212.
2. Sei Y, et al. (2010). Epistatic and functional interactions of Catechol-O-Methyltransferase (COMT) and AKT1 on Neuregulin1-ErbB signaling in cell models. PLoS ONE, 5, 1-14.
3. Sei Y, et al. (2007) Neuregulin1 induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms. Mol Psychiatry, 12, 946-957.
4. Chen J, et al. (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Human Genetics, 75, 807-821.
5. Zammit S, et al. (2010) Individuals, schools, and neighborhood: a multilevel longitudinal study of variation in incidence of psychotic disorders. Arch. Gen. Psychiatry, 67, 914–922
6. 
Raznahan A, et al. (2011). Catechol-o-methyl transferase (COMT) val158met polymorphism and adolescent cortical development in patients with childhood onset schizophrenia, their non psychotic siblings, and healthy controls. NeuroImage, 57, 1517-1523.
7. Pitcher GM, at al. (2011). Schizophrenia susceptibility pathway neuregulin 1 ErbB4 suppresses Src upregulation of NMDA receptors. Nature Medicine, 17, 470-478.
8. Ucok A, et al. (2010). COMT Val158Met polymorphism is related with interpersonal problem solving in schizophrenia. European Psychiatry, 25, 320-322.
9. Boot E, et al. (2011). Dopamine metabolism in adults with 22q11 deletion syndrome, with and without schizophrenia – relationship with COMT Val108/158 Met polymorphism, gender and symptomatology. Journal of Psychopharmacology, 25, 888- 895.
10. Buonanno A. (2010). The neuregulin signaling pathway and schizophrenia: From genes to synapses and neural circuits. Brain Research Bulletin, 83, 122-131.
11. Caspi A, et al. (2005). Moderation of the effect of adolescent onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene environment interaction. Biol Psychiatry, 57, 1117–1127.
12. [Image 1. Frontal composite variability of normal and schizophrenia brains by gender]. Retrieved March 31st, 2014, from: http://www.schizophrenia.com/research/schiz.brain.htm
13. [HowCast]. (2013, August 22nd). What Causes Schizophrenia? | Schizophrenia. Retrieved from https://www.youtube.com/watch?v=iuquAP3R-Ik.
14. [Figure 4: Schematic illustration of the approximate timing of the development of the human brain, functional abilities, and impact of environmental exposures]. Retrieved March 31st, 2014, from http://www.nature.com/nature/journal/v468/n7321/full/nature09563.html
15. [The Role of Genetic and Environmental Factors in the Development of Schizophrenia]. Retrieved March 31st, 2014, from: http://www.psychiatrictimes.com/schizophrenia/role-genetic-and-environmental-factors-development-schizophrenia/page/0/3
16. [Howdini]. (2013, October 22nd 2012). What causes schizophrenia?. Retrieved from https://www.youtube.com/watch?v=x4iijA9RqGs.

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