Is Schizophrenia genetic, neurodevelopmental or neurochemical

What is the genetic basis for schizophrenia?
Identical twins have a 48% risk if one of the twins develops schizophrenia, general population is only 1%
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Twin studies example
Finnish twin study: correlation of .84 in MZ and .34 in DZ
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Maudsley Twin study
.81 in MZ and .31 in Dz
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Adoption study: Oregon
50 children born from schizophrenia mother, adopted by parents with no history of schizophrenia: 10.6% rate of schizophrenia, same rate as if they were reared by mothers with schizophrenia
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Danish study
Sharing genes but not environment had 10 times higher risk. sharing environment but not genes gave no risk. Found 7.9% in first degree biological relatives compared to .9% in controls (No relatives)
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Rosenthal et al (2006)
found that 31.6% were diagnosed as schizophrenic and these were children of schizophrenics but were adopted by normal functioning parents.
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This is compared to?
17.8% for the control group (biological parents had no schizophrenic history and adopted parents did not either).
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Rees et al (2015)
Alleles which are not inherited so newly arising (de novo) mutations have been shown to contribute to the risk of schizophrenia.
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Increased paternal age at conception correlates with what?
with the number of de novo mutations observed in an individual
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The CNV de novo mutation rate was found to be what?
Significantly elevated in schizophrenics (about 5%) VS controls (About 2%) with some evidence for a higher rate among patients with no family history of the disorder
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What is the Genome Wide Association studies (GWAS)
o Purcell et al (2014) suggest many rare disruptive mutations across many genes and schizophrenia working group consortium
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Evidence about 22q?
 Velo-Cardiofacial Syndrome: Genetic disorder due to missing part of chromosome 22q11. It can cause cleft palate, heard defects and distinctive facial features (e.g. elongated face, small nostrils, flat cheekbones).
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What is the prevalence of schizophrenia?
25 times that in the normal population
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Identification does not mean what?
cause – need experiments to show a r ole in disorder and an actual causation
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What did Picker (2005) suggest?
Candidate genes such as DISC1, DAOA and PRODH have a role in genesis of schizophrenia
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Neurodevelopmental hypothesis
- Disruption of brain development during early life underlies the later emergence of psychosis during adulthood
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Two hit hypothesis
and Environment both contribute to schizophrenia
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What led to dopamine dysregulation?
- Subtle motor, cognitive and social deficits which leads to social anxiety, quasi-psychotic ideas (chronic social adversity especially from drug abuse
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What do hippocampal cell changes lead to?
- Hippocampal Cell Changes: cellular disarray in hippocampus of schizophrenic
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Seasonality?
more schizophrenics are born between February and May. Sham et al (1992): 63 schizophrenic births 5 months after the start of an epidemic. There is an increase in schizophrenic births following influenza epidemic.
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Kety et al (2002)
o P was asked to follow a target (small circle) that moved sinusioidally. o Eye tracing made by schizophrenic was significantly more irregular than control P
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What does this suggest?
o Suggests low gain pursuit with frequent catch-up saccadic eye movements
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Immune system
o Genes involved in immune responses have been shown in GWAS studies to be different between large patients groups compared to controls
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What do animal models show?
inducing infection in pregnant mothers (rats and mice) the offspring show behavioural abnormalities and neurochemical abnormalities that are reversed by antipsychotic drugs
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A family of soluble proteins that play an important role as systematic what?
mediators of the host response to infection, are critically involved in the inflammatory response to non-infectious agents and insults, and are contributors to normal development and function of the CNS
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They might be a mechanism through which?
maternal infection produces abnormal brain abnormality which increases risk for schizophrenia
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Zuckermann et al (2003)
Poly I:C is used to mimic viral exposure because it elicits immune responses similar to those observed during viral infection, most notably by inducing the release of proinflammatory cytokines
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What was disrupted?
Latent inhibition, there was enhanced stimulated dopamine release at 90 days
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Walsh et al (2008)
suggest that individually rare structural variants contribute to schizophrenia.
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What is novel deleion?
Novel deletions and duplications of genes were present in 5% of controls compared with 15% of schizophrenics and 20% of young-onset schizophrenics.
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Mutations in cases disrupted genes how?
disproportionately from signalling networks controlling neurodevelopment, including neuregulin and glutamate pathways
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What does this suggest?
multiple individually rate mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.
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What is glutamate?
- Glutamate is the major excitatory neurotransmitter with the subtypes NMDA, AMPA/Kainate and Metabotropic
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Schizophrenia is caused by?
reduced function of NMDA glutamate receptors resulting in reduced glutamate transmission
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Kim (1980)
discovered reduced glutamate in cerebrospinal fluid in patients with schizophrenia. Phencyclidine and Ketamine (NMDA antagonists) produce symptoms of schizophrenia (negative and positive symptoms).
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Harrison et al(2003)
suggested that genes that have recently been associated with an increased risk for schizophrenia
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What was suggested can influence the function of modulatory sites
NMDA receptor or intracellular-receptor interacting proteins that link glutamate receptors to signal transduction pathways
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Clinton and Meador Woodruff (2004)
Postmortem studies show changes in glutamate receptor binding, transcription and subunit protein expression in the prefrontal cortex, thalamus and hippocampus of subjects with schizophrenia
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What are examples?
decreases in NR1 subunits of the NMDA receptor in hippocampus and frontal cortical areas.
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What do glutamate neurons regulate
function of other neurons that have been strongly implicated in the pathophysiology of schizophrenia
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For example?
bursting of dopamine neurons, which is thought to be an integral component of their proper response to environmental stimuli, is dependent on activation of NMDA receptors on these neurons.
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D2 receptors are localised where?
presynaptically on glutamate terminals and work to inhibit the release of glutamate, reduced D2 receptor function produces modest increases in glutamate release.
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Ripke (2014)
studied 36,989 cases of schizophrenia and found associations at DRD2 and several genes involved in glutamatergic neurotransmission. This supports the hypothesis.
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What is schizophrenia caused by?
overactivity of dopaminergic synapses likely in the mesolimbic pathway coming from the ventral tegmental area.
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Weinberger
Schizophrenia (positive symptoms) are caused by an overactivity of dopaminergic synapses likely in the mesolimbic pathway coming from the ventral tegmental area consequent to hypoactivity of dopaminergic synapses in prefrontal cortical regions (negat
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Dopamine hypothesis
Tyrosine -> DOPA -> Dopamine -> DOPAC or Noradrenaline
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What are cognitive, negative and affective symptoms?
Mesocortical underactivity
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Overactivity of dopamine where?
In the middle of the brain can cause underactivity of dopamine in the prefrontal regions of the brain
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Pre frontal corte
Loss of neurons in the dorsolateral prefrontal cortex reduces its inhibitory effects on release of DA in the Nucleus Accumbens (negative symptoms).
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Increased release of dopamine?
in the nucleus accumbens (positive symptoms).
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Meltzer and Stahl (1976)
believe that some and maybe even most schizophrenics will have the equivalent of hyperactivity of DA neurons
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where is this hyperactivity probably be?
secondary to some other basic defect that allows DA activity to be transiently increased during periods of increased CNS arousal created by excessive environmental demands.
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Twin studies example

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Finnish twin study: correlation of .84 in MZ and .34 in DZ

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Maudsley Twin study

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Adoption study: Oregon

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Danish study

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