Article Final - Schizophrenia & epigenetics

Question 1

Positive symptoms define.

Answer 1

additive

Question 2

Negative symptoms define.

Answer 2

taken away/removed

Question 3

Positive symptoms list of schizophrenia

Answer 3

1. hallucinations
2. psychosis
3. mania

Question 4

Negative symptoms list of schizophrenia

Answer 4

1. anhedonia
2. social withdrawal

Question 5

What category do cognitive symptoms fall under?

Answer 5

negative

Question 6

cognitive symptoms in schizophrenia

Answer 6

working memory impairment

Question 7

What neurotransmitter is generally associated with positive symptoms in schizophrenia?

Answer 7

dopamine

Question 8

What neurotransmitter is generally associated with negative symptoms in schizophrenia?

Answer 8

1. abnormal dopamine signaling
2. complicated interaction b/w GABAergic signaling and hypoactive NMDA function in PFC (decreases glutamate), hippocampus, and certain neurons in the amygdala

Question 9

What brain regions and morphology changes are responsible for cognitive symptoms in schizophrenia?

Answer 9

1. PFC & hippocampus (learning & memory)
2. Reduction in the # and complexity of neuronal connection in the cortex suggesting aberrant synaptic pruning during late stages of neurodevelopment
3. Reduced dendritic spine count and complexity in the PFC

Question 10

Why are antipsychotics like clozapine used to treat schizophrenia

Answer 10

antipsychotics that target D2 receptors induce dopamine neurons inactivation or block depolarization (treatment with amphetamines increases hyperactivity and other psychosis-relevant behaviors & clozapine treatment reverses these effects getting rid of pos. symptoms and making neg. symptoms worse)

Question 11

What is the basis for the dopamine hypothesis in schizophrenia?

Answer 11

hyperactivity of DA system may be related to reduced inhibitory neuronal function in the hippocampus and VTA (increase dopamine leads to pos. symptoms and an increase in GABA output & Decrease in places that receive GABA)

Question 12

What is COMT and what does its gene product do?

Answer 12

Catechol-O-methyltransferase - assists in clearing DA from the synapses - COMT-158MAT polymorphism negatively impacts working memory and reduced pre-frontal levels (anything that dopamine effects)

Question 13

Why does excess dietary folic acid (prenatally) increase risk for schizophrenia?

Answer 13

Increases hypomethylation

Question 14

MTHFR

Answer 14

A mutation in this gene is found in 60% of schizophrenia and autism patients - MTHFR metabolizes folic acid into a methyl group, which can be used for methylation and can affect gene expression - in someone with a mutation here it will reduce the activity of MTHFR which can lead to hypomethylation (same effect with folic acid intake and pregnancy)

Question 15

What evidence is there for the glutamate hypothesis for schizophrenia?

Answer 15

Review

Question 16

What is GAD1 and how does it relate to schizophrenia?

Answer 16

GAD1 is an enzyme that synthesizes glutamate to GABA and is reduced in schizophrenic brains (thereby reducing the levels of GABA)

Question 17

What is PVALB and how does it relate to schizophrenia?

Answer 17

Parvalbumin neurons are considered crucial to the pathogenesis of schizophrenia - strong association of the regulation of NMDA signaling (interneuron that modulates glutamate signaling - possibly affects wiring - loss of PVALB neurons and glutamate signaling)

Question 18

What evidence exists for aberrant DNA methylation in schizophrenia?

Answer 18

Modification of CPG islands and TET enzyme alteration lead to transcriptional depression. There are numerous changes in DNA methylation at differentially methylated regions. Several DNMTs are upregulated in patients resulting in hypermethylation and down-regulation of diseased genes (BDNF, GAD1, and more)

Question 19

What might be the result of hypermethylation and subsequent downregulation of BDNF?

Answer 19

1. Expression of DNMTs are upregulated in the brain of schizophrenia pts, resulting in hypermethylation and downregulation of schizophrenia-associated genes including BDNF and others.
2. GADD45b binding to the BDNF promoters leads to major psychosis and reduced expression

Question 20

Use of Valproic acid (VPA) to treat schizophrenia suggests what about histones in schizophrenia/

Answer 20

histone regulation may play an important role in disease pathogenesis as HDAC inhibitors can reverse the effect of postnatal stress (overactive HDAC leads to chromosomes being tightly wound which leads to gene expression decrease)

Question 21

Based on information about HDAC1 in schizophrenia, why is a drug like VPA so useful?

Answer 21

fewer off-target effects

Question 22

What are aberrant histone mods in schizophrenia?

Answer 22

1. histone 3 dysregulation leads to GAD1 expression regulation which reduces expression of genes typically associated with neuronal metabolism
2. abnormal increase in heterochromatin due to an increase in H3K9 methylation and decrease in H3K9 acetylation
3. heterochromatin association with histone methylation is increased in cortical tissue

Question 23

There is a major association between miRNA and schizophrenia. DICER1 is affected in schizophrenia… how does this affect miRNAs?

Answer 23

plays a major role in miRNA processing and is associated with schizophrenia cases that are associated with copy number variation as with nearby miRNAs (find a lot of primer but not mature since no DICER1 for cleavage)

Question 24

What 3 miRNAs are implicated in schizophrenia?

Answer 24

1. miR-132
2. miR-137
3. miR-181b

Question 25

Why is it important that 3 miRNAs are implicated in schizophrenia?

Answer 25

hundreds of genes that can be affected

Question 26

How is there “crosstalk” between miRNAs and other epigenetic modifications?

Answer 26

All members of the miR-132/MECP2/miR-137/BDNF network are subject to epigenetic regulation at multiple levels (review the diagram – schizophrenic brains have hypofrontality and have less phosphorylation of CREB and decrease in miR132 so getting DNA hypermethylation and increase HDAC1 and remove acetyl group which leads to heterochromatin- when MECP2 increases we see downregulation in miR-137 and the whole reason its involved is because of miR-132)

Question 27

Does schizophrenia have a genetic component?

Answer 27

Schizophrenia is heritable and does have a genetic component, but although this is the case the phenotypic expression of the disorder is not only based on genetics. The onset of the disease is caused by not only risk alleles, but also environmental risk factors

Question 28

What are some environmental factors in schizophrenia?

Answer 28

1. prenatal and postnatal stressors
2. paternal age
3. cannabis use

Question 29

What are some epigenetic mechanisms altered in schizophrenia?

Answer 29

1. DNA methylation
2. Histone post-transcriptional modification
3. Regulation of chromatic structure
4. miRNA regulation of signaling pathways

Question 30

What overlap exists between schizophrenia and other disorders both in behavioral phenotypes and genetics/epigenetics?

Answer 30

The microRNA regulation of signaling pathways has an effect on both DNA methylation and histone activity – this also plays a role in neurodevelopment disorders since they are capable of regulating large numbers of genes at once – in other words epigenetic mechanism mediate the interaction b/w genetic risk alleles and environmental factors by dynamic modification of the genome in response to positive or negative environment stimuli.