Epigenetic regulation of brain development and function Flashcards
1
Q
What is long term potentiation (LTP)? (3)
A
- The strengthening of a synapse after frequent use
- Molecular basis for memory formation
- Involves upregulation of post-synaptic neurotransmitter receptors
2
Q
How does LTP occur? (6)
A
- Glutamate binds to post-synaptic receptors
- Ca2+ influx
- CaMKII activation (kinase)
- CREB transcription factor phosphorylation
- CRE-containing promoter activation
- Altered synaptic gene expression and altered synapses
3
Q
What is detected in response to synaptic activity-induced Ca2+ influx? (3)
A
- Npas4 transcription factor expression (likely to be a target of phospho-CREB)
- C-fos expression
- Phospho-CREB
4
Q
What induces C-fos expression? (4)
A
- Synaptic activity (Ca2+)
- BDNF
- NT3/4
- NGF
5
Q
What is pentylenetetrazol (PTZ)?
A
Seizure-inducing agent which causes rapid neuronal firing
6
Q
How does LTP increase post-synaptic receptors? (2)
A
- Synaptic activity-dependent transcription factors recruited to target genes
- Causes encoding of neurotransmitter receptor subunits/factors that mobilise receptor subunits to the synaptic membrane
7
Q
What is the function of BDNF?
A
Required for activity-induced enhancement of axon outgrowth
8
Q
Where are memories created and stored?
A
Hippocampus
9
Q
How are histone modifications in memory studied? (8)
A
- Contextual fear memories studied via behavioural assay
- Put mouse in a new environment and administer a mild electric shock
- Return to home cage
- Return again to the new cage, mouse freezes as a memory response, measure the freezing response without shock
- Longer freezing means stronger memory
- Memory freezing response diminishes over time and eventually disappears
- Collect tissues
- Way to study memory formation and persistence
10
Q
How is histone deacetylase 2 (HDAC2) involved in memory? (3)
A
- HDAC2 knockout animals freeze for longer = stronger memory, also have more hippocampus dendrite growth
- HDAC2 overexpression reduces freeze = weaker memory, have fewer dendrites
- HDAC2-sensitive histone acetylation promotes memory formation and retrieval
- HDAC2 specifically binds to promoters of neural genes implicated in synaptic regulation and deacetylates
11
Q
What is CBP? (2)
A
- CREB-binding protein
- A histone acetyltransferase (HAT)
12
Q
What is the structure of CBP? (3)
A
- Histone acetyltransferase domain acetylates multiple lysines in core histones
- Bromodomain binds to acetylated lysines in core histones
- PHD finger binds to H3K4me (this modification often found alongside histone acetylation)
13
Q
What is caused by CBP mutation? (2)
A
- Mutations deactivate the histone acetyltransferase domain (can be nonsense, missense or deletions)
- Heterozygosity for these mutations causes Rubinstein-Taybi syndrome (RTS) (severe neurological disorder)
14
Q
What is Rubinstein-Taybi syndrome (RTS)? (2)
A
- Severe neurological disorder which causes microcephaly, short stature, developmental delay, behavioural abnormality, mental impairment
- Caused by heterozygous mutation in CBP gene
15
Q
What is the role of CBP in memory formation? (3)
A
- Heterozygous CBP knockouts have very poor freeze memory response
- Also fail to activate c-fos in response to synaptic activity, also has lower acetylation
- CBP promotes memory formation and retrieval, promotes H2B acetylation and facilitates transcription of the immediate-early activity-regulated gene c-fos in the hippocampus
