6. Schizophrenia Flashcards by Barbora Buc

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

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WHat are SCZ symptoms?

SCZ symptoms:
- hallucinations
- delusions
- thought disorder
- movement disorder
- inappropriate emotional expression

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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

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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

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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

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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)

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What is the level of SCZ heritability?

There is a familial genetics component in SCZ - in monozygotic twins 48% risk of SCZ was shared

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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

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What are the predictor factors of SCZ?

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What are the approaches to study SCZ?

SCZ neurobiology studied in:
- pharmacology
- brain imaging studies
- post-mortem sudies
- genetics

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What are the proposed hypotheses for SCZ development mechanism?

Hypotheses for SCZ development mechanism:
- dopamine
- glutamate
- neurodevelopment

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Explain the dopamine hypothesis behind SCZ

Dopamine (DA) hypothesis - due to excess dopamine activity - drugs that block dopamine reduce positive symptoms

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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

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Explain the glutamate hypothesis in SCZ development

Glutamate hypothesis suggests - problem is the deficient glutamate activity - lack of it

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What are the problems with Glu hypothesis of SCZ?

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Explain the neurodevelopmental hypothesis in SCZ development

Neurodevelopmental hypothesis behind SCZ suggests that abnormalities in prenatal and neonatal development in NS cause SCZ

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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

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Explain macro abnormalities observed in SCZ brains

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Explain micro abnormalities observed in SCZ brains

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What are the changes in cortical region of the brain in SCZ?

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What are the changes in the white matter of the brain in SCZ?

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Explain SCZ as a disease of synaptic function

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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?

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What are the current treatment approaches for SCZ?

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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

6. Schizophrenia Flashcards

(47 cards)