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I have been reading a fascinating paper: Valproate reopens critical-period learning of absolute pitch

18 individuals were given Sodium Valproate (VPA) for a fortnight during which they trained on a pitch-training game. Results suggest that VPA reopens the plasticity window that normally closes by adolescence.

However, the paper seems to suggest that the exact mechanism of action is unknown.

Valproic acid is believed to have multiple pharmacological actions, including acute blockade of GABA transaminase to enhance inhibitory function in epileptic seizures and enduring effects on gene transcription as an histone deacetlyase (HDAC) inhibitor (Monti et al., 2009). Of relevance here is the epigenetic actions of this drug, as enhancing inhibition does not reactivate brain plasticity in adulthood (Fagiolini and Hensch, 2000), but reopening chromatin structure does (Putignano et al., 2007). While systemic drug application is a rather coarse treatment, the effects may differ dramatically by individual cell type (TK Hensch and P Carninci, unpublished observations). VPA treatment mimics Nogo receptor deletion to reopen plasticity for acoustic preference in mice (Yang et al., 2012), suggesting a common pathway through the regulation of myelin-related signaling which normally closes critical period plasticity (McGee et al., 2005). Future work will address the cellular actions of VPA treatment in the process of reactivating critical periods. Future MRI studies will also be needed to establish whether HDAC inhibition by VPA induces hyperconnectivity of myelinated, long-range connections concurrent with renewed AP ability (Loui et al., 2011).

So it is saying that the standard use of VPA is to increase GABA levels (which keeps firing rate down -- it is used as an antiepileptic), however it also acts as an HDAC inhibitor, which means it causes unwrapping of chromatin and consequently increased mRNA transcription, maybe even transcription of genes that would normally be entirely deactivated in an adult.

So my guess is that some protein is getting produced that messages neurons to generate new axon/dendrite growth and/or new synaptic connections.

Can anyone clarify how VPA might accomplish plasticity?

EDIT (one month later): I have more detail, but I still can't quite make the connection. Here goes:

Neurites get wrapped by myelin/oligodendrocyte, which produces and exudes some of the chemical messagers {Nogo, OMgp, MAG}. The membrane surface of the neurite contains nogo 66 receptors (NgR-s) that get triggered by these messagers and inform the neuron to inhibit axon-growth. Somehow the 'HDAC inhibition' property of VPA is unwinding DNA enough to alter transcription rates of certain proteins, and one of these must be disabling the NgR.

But how is this happening?

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As far as I can see this paper is being a little misleading, by saying "VPA mimics Nogo-66 receptor deletion".

The action of VPA doesn't seem to be related to this receptor.

It seems that blocking this receptor and applying VPA both increase plasticity, but via different mechanisms.

VPA seems to facilitate LTP through increased availability of relevant proteins (as an HDAC inhibitor, it "loosens/unwinds" DNA, allowing for increase in protein transcription). And by increasing protein transcription across the board, it may be increasing the availability of proteins that promote synapse formation.

The principal problem with growing new structure is, as hinted at the end of the question, that the adolescent/adult brain secretes a chemical that gets picked up by Nogo 66 receptor, which signals to collapse the axon growth cone.

It's why adult humans can't recover from spinal injuries. The axons won't reconnect.

It so happens that a small molecule Nogo Antagonist has recently been developed by Professor Strittmatter. He was kind to reply to my query, and I learned that this molecule is currently in the early stages of FDA approval. It's a very exciting discovery!

I would caution anyone considering taking VPA to balance it with a beta-blocker (e.g. omeprazole). It is an acid, and if not balanced with something to reduce the stomach's ability to produce acid, risks acid reflux, which may force a change of diet, and be longterm/permanent. So, DYOR.

Also of note is that (again discovered by Strittmatter) Ibuprofen has been found to also interrupt the signalling pathway that leads to axon growth collapse. But it requires a high dosage, and ibuprofen also causes a similar imbalance.

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    $\begingroup$ Can you provide a link to the paper regarding the receptor antagonist? Also, the anecdotal evidence seems to be very unscientific and I recommend that it be removed. $\endgroup$
    – March Ho
    May 10, 2015 at 5:28
  • $\begingroup$ @MarchHo ncbi.nlm.nih.gov/pubmed/12037567 -- also, that is a terrible idea to remove valuable information (that, as it happens, has been scrutinised by an Oxford educated medical professional). Anyone considering taking VPA should be forewarned and educated. $\endgroup$
    – P i
    May 10, 2015 at 10:55
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    $\begingroup$ @Pi anecdotes as basis for medical advice aren't really appropriate for this site - otherwise very good answer that I'd be happy to upvote. $\endgroup$
    – Rory M
    May 27, 2015 at 17:54
  • $\begingroup$ ok 7 years later, I agree. I have cleaned the answer, and also filled in a couple of blanks from memory. $\endgroup$
    – P i
    Mar 5, 2022 at 8:59
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    $\begingroup$ Please add references while you're on it. -1 $\endgroup$
    – AliceD
    Mar 9, 2022 at 8:11

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