Figure 4

Schematic model for the rescue of associative plasticity in aged neural networks by inhibition of HDAC3.

(A) In aged neural networks, induction of late-LTP by STET marks synapses (S1) with a synaptic ‘tag’ and induces protein synthesis. The subsequent induction of E-LTP in the neighbouring synapses (S2) by WTET leads to synaptic competition for the available plasticity realted products (PRPs). Here, the synapse S1 completely utilizes the PRPs for its own maintenance without sharing it with the other synapses in S2. Thus, there is no late-associativity between these synapses. Increased activity of HDAC3 is one of the possible contributing factors. The active HDAC3 deacetylates its histone and non-histone (NFκB, CREB binding protein CBP, myocyte enhancer factor 2 MEF2) targets. The active HDAC3 prevents the nuclear gene transcription by promoting the export of NFκB from the nucleus; decreasing the CBP histone acetyltransferase (HAT) activity; and by terminating the MEF2-dependent transcription of plasticity genes. (B) The inhibition of HDAC3 activity prevents the export of NFκB from the nucleus. As a result, NFκB signaling cascade is activated that results in the induction of numerous gene targets, many of which code for the plasticity proteins such as BDNF and CaMKII. In addition to this, CREB-mediated gene transcription and MEF2-dependent transcription of structural plasticity genes is also enhanced. Subsequently, the PRPs get globally distributed in the neuron and are shared between both the active synapses (S1 and S2) resulting in a stable plasticity and late-associativity (adapted and modified from Chen et., 2001; McQuown and Wood 2011).