Neuroepigenetics mind map continued
Skepticism of neuroepigenetics
- Rats who were nurtured did not have theur corticol receptor gene DNA methylation go up, rather for non nurtured mice it went down.
Epigenetic changes only occured on some genes in some areas of the brain, but not others.
Epigenetics changes were very small.
Scientists are worried about correlation does not equal causation
Different areas of the brain are separate and respond to different stimuli so this is not a problem
This was the same for the mice and arginine vasopressin.
Active DNA methylation is due to an OH group being added to 5-methylcytosine, having the same effect as demethylation.
Other type of DNA methylation is the fading out of methylation as DNA is replicated and methylation does not occur on the new strand.
Because of the addition of the OH group forming 5-hydroxymethylcytosine, MeCp2, a methylation reeader, did not recognise this is a methylated DNA.
It as only been with very recent techniques that 5-hydorxymethylcytosine has been detected so it is possible that the detected lowered methylation levels are to do with active methylation.
The cortex and hippocampus are involved in memory storage.
The cortex is for long storage memories and the hippocampus is where memories are temporarily processed, before being deleted or transferred to the cortex.
Evolutionarily, these makes sense as remembering everything you have ever done is too much but having onlly short term memory is not good too.
Experiments on memory are difficult because not enough is known abou tht ebrain.
Memory involves long term changes in gene expression and the connections between neurones so epigenetics may explain this.
DNA methylation and histone modifications in mammals are important in learning and in memory.
DNMT3A and DNMT3B are involved in learning and in memory and treating rats with DNMT inhibitors affects the hippocampus and cortex.
In Rubenstein- Taybi syndrome, histone acetyltransferase is a mutated gene. Mental retardation is a common sympton of this disorder and mice with lower levels of histone acetylation in their hippocampus had problems with their memory.
When these mice were given SAHA, an HDAC inhibitor, their memory improved.
SAHA is specific to many different histone deacetylases but aprticulary ot HDAC1 which is expressed mainly in neural stem cells and glial cells and HDAC2 found mainly in neuronal cells.
In mice who have over expressed HDAC2, their long term memory is poor an but their short term memory is fine. Mice whose neurones do not express any HDAC2 seem to have very good memories, suggesting HDAC2 decreases hoe good your memory is.
Overexpression of HDAC2 led to fewer neural connections but those lacking HDAC2 had very good memories. SAHA improves memory of normal mice, presumably because it dampens HDAC expression and then improved memory.
Mice who had stimulating fun environments had more histone acetylation and their memory improved further when treated with SAHA.
SAHA and 5-aza-cytidine could be used for much more than just cancer treatment. Alzheimer's treatment may be possible with these drugs.
However there are sever side effects my own thought: probably because DNA methylation targeting is broad and methylation patterns of other genes is affected?). These drug may be ok for a terminally ill, near end of life cancer patient who wants to improve their QoL but certainly not for an early stage dementia patient who still has a good quality of life and is not near death of of course not for the general population.
Sodium valporate is an HDAC and used to treat epilepsy however is weak and is not strong enough to improve memory.
Addiction could be treated with epigenetic therapies
In mouse studies it was found that drug addcited mice had changes in their DNA methylation patterns and therefore how their methylation was read by MeCp2- these long lasting gene expression underpin addiction.
The molecular pathway that this happens by is not very well understood.
Epigenetic drugs used to treat children would be ideal but could be ethically debated.
Trials would also need to go on for decades to see the effect of drugs throughout their children's lives and would not be profitable for drug companies.
It was found in mice that Grb10 (a gene) when switched off makes mice aggressive (like an aggressive drunk) but when this is switched on again, mice become less overly aggressive