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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is a rather coarse treatment, the effects may differ dramatically by individual cell type (TK Hensch and P Carninci, unpublished observations).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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This paper might be of some help ncbi.nlm.nih.gov/pmc/articles/PMC3907704 –  Devashish Das Jul 23 '14 at 17:14

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