AM - Schizophrenia IIII Flashcards
What are the genetic bases for schizophrenia? (2)
- Linkage analysis further implicates cortical dysfunction
- Hundreds of genetic susceptibility factors have been linked to schizophrenia
What insights are provided by chromosomal abnormalities in schizophrenia? (2)
- Association with chromosomal microdeletion syndromes.
- Rare familial variants of schizophrenia
What is an example of a rare familial variant in schizophrenia?
Velocardio facial syndrome (VCFS)
What are features of VCFS? (5)
- Microdeletion of 1.5 to 3 Mb in chromosome 22 (includes ~30 genes).
- Increased incidence of psychiatric disorders, including schizophrenia.
- Clear morphological changes.
- Higher incidence of Chr 22 deletion in the schizophrenic population.
- Understanding pathways these genes influence may lead to drug repurposing
What are candidate genes?
Candidate genes are genes that are hypothesized to play a significant role in the development of a particular trait, condition, or disease based on their known biological functions, genetic association studies, or their location in the genome.
What candidate genes are implicated in schizophrenia? (2)
Catechol-O-methyl-transferase (COMT): a metabolic enzyme for dopamine, involved in dopamine regulation.
DISC1 (Disrupted in Schizophrenia 1): a gene linked to schizophrenia, major depression, and bipolar disorder.
What is the role of COMT?
This enzyme catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to a hydroxyl group on a catechol compound, resulting in the formation of an O-methylated catechol and S-adenosylhomocysteine (SAH).
What are the two alleles of COMT in humans?
- Valine 108 (val-108):
- Methionine 108 (met-108):
How does COMT activity vary between its alleles?
Valine 108 (val-108):
* Produces a more stable enzyme.
* Associated with faster dopamine breakdown, leading to lower synaptic dopamine levels.
Methionine 108 (met-108):
* Produces a less stable enzyme.
* Slower dopamine breakdown, resulting in higher synaptic dopamine levels.
What are limitations of early studies on DISC1? (2)
- Small sample sizes.
- Lack of consideration for environmental factors.
What are the key roles of DISC1 in the brain? (5)
- Neuronal proliferation
- Neuronal migration
- Regulators of key signalling pathway
- Synapse formation and maintenance
- Spine regulation
What is neuregulin, and how is it linked to schizophrenia? (4)
- A growth factor encoded on chromosome 8 linked to schizophrenia.
- Regulates neuronal differentiation and migration.
- Evidence: Increased mRNA levels in schizophrenic brains from post mortem.
- Hypothesis: Increased neuregulin signaling reduces NMDA receptor function, contributing to schizophrenia.
What hypothesis explains cortical-subcortical dysfunction in schizophrenia? (2)
- Cortex normally inhibits subcortical activity.
- Dysfunction leads to excessive subcortical activity and cross-talk with the cortex, resulting in disorganized actions.
What evidence links the PFC and subcortical dopamine systems to schizophrenia? (6)
- Hypofunctionality in brain imaging.
- Altered cytoarchitecture in postmortem (PM) brains.
- Decreased D1 receptor density in PM brains.
- Lesions in primates cause negative symptoms.
- DISC1 and COMT are highly expressed in the cortex.
- DISC1 implicated in neuronal migration and interacts with proteins which are mutated in lissencephaly
What conclusions guide future schizophrenia research and therapy? (4)
- Improve understanding of genetic and environmental factors.
- Develop better experimental models to study the disorder.
- Aim for early, accurate diagnosis.
- Create therapies to mitigate schizophrenia’s severe impacts.
