Akhtar MW, Raingo J, Nelson ED, Montgomery RL, Olson EN, Kavalali ET, Monteggia LM.
Histone deacetylases 1 and 2 form a developmental switch that controls excitatory synapse maturation and function.
J Neurosci. 2009 Jun 24;29(25):8288-97.
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Histone deacetylases (HDACs) are increasingly recognized as playing important functions in learning and memory, and cumulative evidence suggests therapeutic applications of HDAC inhibitors (HDACis) for CNS disorders such as Rubinstein-Taybi syndrome and Huntington disease. Most of the seminal studies were carried out using nonselective HDAC inhibitors, and thus an important next step is the elucidation of which HDACs play important roles in the CNS.
In this paper, Monteggia and colleagues examined the functional role of HDAC1 and HDAC2 in the regulation of synapse formation and maturation. General HDACi treatment largely facilitated the maturation of excitatory synapses and increased the synapse number, in line with our previous reports (Fischer et al., 2007; Guan et al., 2009). Interestingly, genetic ablation of both HDAC1 and HDAC2 is required to mimic this effect. However, in contrast, in the mature neuron, decreased HDAC2 results in the attenuation of basal excitatory neurotransmission.
These interesting findings reinforce recent findings by our group (Guan et al., 2009) that Class I HDACs, especially HDAC2, are major targets of general HDACis in the CNS. It is also interesting that ablation of both HDAC1 and HDAC2 is required to facilitate synapse formation in developing neurons, which suggests functional overlap during this period. A similar scenario regarding HDAC1/HDAC2 is encountered during developmental neuronal specification, as reported previously by the same group (Montgomery et al., 2009). In contrast, the two enzymes do not seem to play redundant roles in mature neurons, again agreeing with our findings (Guan et al., 2009). On the other hand, based on the authors’ observation of inhibition on miniature excitatory postsynaptic currents (mEPSCs) by chronic treatment with the HDAC inhibitor Trichostatin A, it is likely that HDACis may have some potential neurological side effects and that selective HDAC2 inhibitors may be therapeutically advantageous. Future studies should explore the mechanisms by which HDAC2 is involved in synaptic maturation and later in mEPSP inhibition.
Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH.
Recovery of learning and memory is associated with chromatin remodelling.
Nature. 2007 May 10;447(7141):178-82.
Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH.
HDAC2 negatively regulates memory formation and synaptic plasticity.
Nature. 2009 May 7;459(7243):55-60.
Montgomery RL, Hsieh J, Barbosa AC, Richardson JA, Olson EN.
Histone deacetylases 1 and 2 control the progression of neural precursors to neurons during brain development.
Proc Natl Acad Sci U S A. 2009 May 12;106(19):7876-81.