The Two-Hit Hypothesis of Schizophrenia Flashcards
What are environmental risk factors of schizophrenia?
winter birth month (OR ~1.2)
urbanicity (~1.5)
What are prenatal risk factors of schizophrenia?
maternal stress
maternal nutrition
maternal infection
delivery complications (neonatal hypoxia)
paternal age
What are genetic risk factors of schizophrenia?
familial risks
biggest risk is someone else in your family having it
What are the stress risk factors of schizophrenia?
childhood abuse/trauma
minority status
not from reliable studies
What is the heritability of schizophrenia?
overall heritability estimated at 83%
How does the developmental phase impact the course of schizophrenia?
schizophrenia has a defined course that starts during the developmental phase
observable traits in the premorbid phase correspond to periods of developmental change in the brain
What is the neurodevelopmental hypothesis of schizophrenia?
schizophrenia is a result of deficits in neural development brought on by a combination of genetic and environmental risk factors
measurable pathologies in SCZ include decreased grey matter volumes especially in prefrontal and temporal cortex, decreased hippocampal volume, increased lateral ventricle volume
developmental course of disease complicates determination of causal/pathological changes and phenomenological changes
causal changes: contributing to disease pathology and/or behavior
phenomenological: resulting from or coincident with pathological changes
What is childhood onset schizophrenia (COS)?
rare presentation of SCZ in childhood or early adolescence
childhood form is contiguous with adult form
4% of SCZ cases occur before age 15
0.1-1% present before age 10
COS patients offer a unique chance to study family associations and developmental changes
What are brain abnormalities in childhood onset schizophrenia?
decreased grey matter volume (especially prefrontal and temporal cortex): progressive change over time
decreased cerebellar volume
decreased hippocampal volume: no progression in volumetric changes
studies have analyzed volumetric changes in healthy siblings (high genetic risk)
What are the anatomical deficits in healthy siblings of childhood onset schizophrenia?
volume differences in grey matter observed in healthy siblings: grey matter normalizes by age 20
cerebellar volume changes in healthy siblings: volume changes do NOT normalize, possible trait marker for SCZ risk
no changes in hippocampal volume observed: hippocampal changes proposed to be state-marker of SCZ (implication for disease course)
What are the results of monozygotic twin studies on schizophrenia?
age of onset in adult SCZ prevents developmental analyses
risk of SCZ in offspring of discordant MZ twins is the same: genetic risk factors are conserved between discordant twins
MZ twins show similar trends in decreased cerebral (grey matter) volume
unaffected twin do not show reduced hippocampal volume, hypoactivity of prefrontal cortex, and cognitive function
discordant twin studies support neurodevelopmental models (environmental impacts on neurodevelopment are required to convert a high-risk to affected SCZ)
unaccounted for role of epigenetics
What are the gene changes in schizophrenia?
no single polymorphism has been identified to explain SCZ, rather numerous genetic risks each with low (but likely cumulative) penetrance
linkage studies (chromosome level analysis) have identified significant hits in 1q42.1, 6p21-22, 22q11.2
microarray and genome-wide association studies have identified numerous changes in genes associated with specific pathways: synaptic function, immune function
What is the relationship between the DISC-1 gene and schizophrenia?
disrupted in schizophrenia-1
identified following linkage analysis study (1q42.1) in juvenile offenders
a number of variations have been correlated with increased risk of SCZ (no single common polymorphism)
What is the relationship between the COMT gene and schizophrenia?
catechol-O-methyl transferase: catabolic enzyme that breaks down dopamine
COMT is located in 22q11 locus (deletion is a risk factor for SCZ)
common SNP (GUG –> AUG, Val158Met) produces a 4x decrease in enzyme activity
val allele: high COMT activity
met allele: low COMT activity
val/met polymorphism is correlated wit structural changes in the PFC
What are pathways in schizophrenia?
large-scale genetic studies have highlighted genetic risks involved in pathways rather than specific genes
pathways involved in glutamatergic synapses and synaptic plasticity are implicated
What is the plasticity related pathway implicated in schizophrenia?
PSD-95 structural protein in post-synaptic density
NMDA receptor signaling complex glutamate receptor implicated in synaptic plasticity
voltage-gated calcium channels involved in Ca2+-induced mechanisms of plasticity
metabotropic glutamate receptors regulate intracellular signaling involved in plasticity
membrane associated guanylate kinases regulatory molecules at the synapse
activity-regulated cytoskeleton associated proteins (ARC) and Actin filament bundle assembly proteins reorganize synaptic structure during plasticity
CYFIP1 and FMRP (fragile X mental retardation complex) involved in transcription regulation of plasticity genes
How are immune pathways implicated to be a schizophrenic risk?
CNV studies implicate an area of chromosome 6 carrying numerous immune genes
in particular 6p21 and the Major Histocompatibility Complex (MHC)
3 genome-wide association studies (GWAS) in 2009 identified 33 significant SNPs from nearly 50,000 patient and control samples
What is the function of the Major Histocompatibility Complex (MHC) in schizophrenia?
MHC complex is expressed developmentally in the CNS and is increasingly recognized for developmental roles
neuronal differentiation
synapse formation
synapse function
synaptic plasticity
activity-dependent refining (synaptic pruning)
What is the two-hit hypothesis of schizophrenia?
a combination of genetic susceptibility and distinct developmental insult prime an individual for full syndrome development
heritability: 83%
environment: 17%
What are the neonatal risks for schizophrenia?
neonatal stress, nutrition, and infection are one of the best studied environmental risks for SCZ
neonatal stressors interact with immune functions and developmental course
What is the relationship between neonatal nutrition and schizophrenia?
occupied Netherlands faced a winter famine in 1944-45: 2-fold increased risk of SCZ in children who were in utero
Great Chinese Famine 1959-61 during the cultural revolution: 2-fold increased risk in famine-stricken areas
What are obstetric risks of schizophrenia?
placental pathology
low birth weight
Rh incompatibility
Pre-eclampsia
numerous non-specific obstetric complications likely have a common component of neonatal hypoxia
How does maternal infection and stress increase the risk of schizophrenia?
maternal infection is a well recognized risk: influenza, toxoplasma gondii, herpes simplex 2, rubella
maternal stress studies initiated by findings occupied Netherlands, the Israel Six-Day war, and the North Sea Flood in the Netherlands
significant risk associated with bereavement during pregnancy (especially loss of spouse)
How is the field of epigenetics helpful in studying risk factors of schizophrenia?
excessive methylation worsens SCZ
discordant MZ twins have methylation differences
methylation of GABA related genes affects SCZ animal models
DNAMT1 (DNA methyltransferase1) levels are altered in some cortical areas in SCZ
DNA methylation changes have been observed in ~100 SCZ associated loci including glutamatergic and GABAergic systems
