6. Schizophrenia Flashcards
What is Schizophrenia (SCZ)?
Schizophrenia - chronic neurodevelopmental disorder that affects how a person thinks, feels, and behaves - often leads to distorted perceptions of reality - manifests in late adolescence / early adulthood - affects many brain regions and functions - genetics + environment cause
Positive symptoms: additional symptoms on top of base disease
Negative symptoms: lack of normal behaviour
WHat are SCZ symptoms?
SCZ symptoms:
- hallucinations
- delusions
- thought disorder
- movement disorder
- inappropriate emotional expression
What is the problem in SCZ diagnosis?
Problems in SZC diagnosis - misdiagnosis:
- no biochemical test
- reliant on self-reporting
- little effective research because can’t pinpoint the ones affected to study them
- symptoms similar to other diseases - bipolar disorder, delusional disorder, psychotic disorder
What are the epidemiological observations on SCZ?
Epidemiological observations on SCZ:
- lifetime prevalence in 1% if population
- present for centuries
- begin in young adult life
- male more frequent
- genetic - runs in families
- trait persist althought should be negatively selected against - SCZ patients usually don’t marry
What is the SCZ disease development course
Begins with subtle abnormalities in social, motor and cognitive skills - oscillations in episodes - constant prevalence of the disease
SCZ a chronic disorder, what are the proportions of different outcomes in pattients?
After 10 years of disease
- 25% completely recovered
- 25% much improved, relatively independent
- 25% improved but need support
- 15% hospitalized, unimproved
- 10% dead (msotly suicide)
What is the level of SCZ heritability?
There is a familial genetics component in SCZ - in monozygotic twins 48% risk of SCZ was shared
What is the role of environment in SCZ development?
SCZ occurs due to genetic + env factors
Env factors:
- prenatal factors: poor nutrition, premature birth, low birth weight, comcplicatios during delivery (hypoxia)
- head injuries
- viral infections
- season-of-birth effect: people born in winter have slightly greater probability of SCZ
What are the predictor factors of SCZ?
What are the approaches to study SCZ?
SCZ neurobiology studied in:
- pharmacology
- brain imaging studies
- post-mortem sudies
- genetics
What are the proposed hypotheses for SCZ development mechanism?
Hypotheses for SCZ development mechanism:
- dopamine
- glutamate
- neurodevelopment
Explain the dopamine hypothesis behind SCZ
Dopamine (DA) hypothesis - due to excess dopamine activity - drugs that block dopamine reduce positive symptoms
What are the problems with DA hypothesis of SCZ?
Problems with DA hypothesis of SCZ:
- direct measurements of dopamine and its receptors don’t strongly support
- time course for effects on symptoms is later than effects on the receptors
- DA dysfunction does not account for all the symptoms
- antipsychotics that are DA receptor antagonists are not fully effective
Explain the glutamate hypothesis in SCZ development
Glutamate hypothesis suggests - problem is the deficient glutamate activity - lack of it
What are the problems with Glu hypothesis of SCZ?
Explain the neurodevelopmental hypothesis in SCZ development
Neurodevelopmental hypothesis behind SCZ suggests that abnormalities in prenatal and neonatal development in NS cause SCZ
What are the structural and functional abnormalities observed in SCZ brains?
- Macro: enlarged ventricles, reduced brain volume and weight, hypofrontality
- Micro: mislocated / clusterred neurons, cell bodies smaller, dendritic alterations, reduction in interneurons, reduction in number and function of oligodendrocytes
Explain macro abnormalities observed in SCZ brains
Explain micro abnormalities observed in SCZ brains
What are the changes in cortical region of the brain in SCZ?
What are the changes in the white matter of the brain in SCZ?
Explain SCZ as a disease of synaptic function
SCZ develops in early adulthood because we are born with more synapses than needed - synapse pruning in early adulthood of unused synapses - only after pruning SCZ seen
What are the main pathologies of SCZ?
What are the current treatment approaches for SCZ?
Current treatment approaches for SCZ:
- drugs: antipshychotics, atypical antypsychotics
- psychosocial: therpay
Explain how typical antipsychotics work
Typical antipsychotics block dopamine receptors (D2R) but also have off-target receptor blocking - side effects
What are the typical anti-psychotic drug side effects?
Typical anti-psychotic drug side effects:
- dopamine: parkinson like symptoms (reversible), tardive dyskes (irreversible)
- Muscarine: Ach (?): peripheral (blurred vision, dry mouth, increased heart rate), central (impaired concenration, confusion)
- Histadine: sedation
Effective against positive symptopms but not so much against negative
Explain how atypical antipsychotics work
Atypical anti-psychotics block D2 receptors and also have off target effects -> side effects
What are the atypical anti-psychotic drug side effects?
Atypical anti-psychotic drug side effects:
- blood disorders (agranulocytosis - absence of neutrophils, neutropenia - absence of WBCs)
- hypo-hypertension
- weight gain
Primarily effective against positive symptoms but not negative
Why are direct glutamate antagonists not used in SCZ treatment?
Direct glutamate antagonists not used because overproduction of glutamate is neurotoxic - glutamate collapse
Alternative - enhance transmission through NMDA receptors
What are additional potential drug targets in SCZ?
Additional potential drug targets in SCZ:
- other neurotransmitter systems: serotonin, acetylcholine
- candidate genes -? still in research
What are the benefits of SCZ gene identification?
Benefits of SCZ gene identification:
- understand aetiology
- improve drug development and testing
- development of definitive diagnostic tools
- undrestanding of interaction with non-genetic risk factors
- insight into normal brain development and function
What is the genetic load in SCZ?
Genetic contribution 40-60% - from identical twin studies - other half environmental
In population 1% risk
10-15% risk for 1st degree relatives
Explain the GWAS findings in SCZ
SCZ - complex trait - many alleles with little impact come together - genes shared with bipolar disorder genes - overlap but also de novo SCZ mutations - but some allelic variation observed - not same genes act in all patients
GWAS genes in linkage disequilibrium - genes involved in:
- immunity - MHC
- glutamatergic neurotransmission
- dopaminergic neurotransmission
=> synaptic biology involved in SCZ
?? Rare genetic factors in SCZ
NMDA
Role of NMDAR synaptic plasticity in SCZ
What are the causes fo NMDAR dysfunction?
NMDAR dysfunction induced by:
- viral infection
- rare mutations
- anti-NMDAR encephalitis
- multiple small effect genes
What is the SCZ development process?
What are the benefits and drawbacks of developing mouse models for SCZ studying?
What is the main problem of using mice for studying SCZ?
Current SCZ diagnosis relies on self-reporting - mice can’t self-report
How to tell if mouse is SCZ? - observe positive and negative symptoms and pathology
How is SCZ induced in rodent models?
What is the role of epigenetics in SCZ?
DNA methylation in SCZ at CpG islands due to stress - genetic susceptibility to environmental factors
What is a genetic mutation that is linked to SCZ?
A balanced translocation between chrm 1 and chrm 11 - linked to SCZ
observed to co-segregate with major mental illness
What is the function of DISC1 protein in SCZ?
DISC1 important in neuronal signaling - integrates with Wnt and cAMP signalling
Decreased DISC1 causes SCZ - generated mouse models with ENU mutations
How can SCZ be induced in mouse models?
Via epigenetics - via stress - ex withdrawal of young mice from their mothers - induced epigenetic control of dopaminergic neurons via glucocorticoids - increased methylation at tyrosine hydroxylase (TH)
Explain the stressed synapse 2.0 hypothesis
Environemntal stresses in SCZ - alterations in synapses
Lecture conclusion
Lecture summary
