Editors' ChoiceNeuroscience

Shuttling Plasticity

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Science Signaling  13 Nov 2012:
Vol. 5, Issue 250, pp. ec295
DOI: 10.1126/scisignal.2003771

Activity-dependent changes in gene expression are involved in synaptic plasticity and contribute to cellular processes that mediate learning and memory. Sando et al. examined the role of HDAC4, a member of the histone deacetylase family that lacks conserved residues required for catalytic activity, in glutamatergic synaptic plasticity. Mutations in the gene encoding HDAC4 that produce a truncated protein have been associated with a form of mental retardation. The abundance of HDAC4 in neurons increased in mice postnatally, a period of rapid synaptogenesis. Inhibition of glutamate receptor signaling or calcium/calmodulin-dependent kinase in cultured neurons increased the nuclear accumulation of HDAC4, consistent with the phosphorylation of HDAC4 promoting its nuclear export and cytosolic retention. Selective inhibition of glutamatergic activity in the forebrain of mice also increased HDAC4 accumulation in the nuclei of neurons. Transcriptional profiling of neurons overexpressing a phosphorylation mutant (HDAC4-3SA) that cannot be exported from the nucleus showed that nuclear HDAC4 functioned as a transcriptional repressor and that many of the repressed genes encoded proteins associated with synaptic function or development. The interaction of HDAC4 with the transcription factor MEF2 was increased when glutamate receptors were inhibited, and deletion of the domain of HDAC4 required for this interaction blocked the repressor activity of HDAC4. Expression of the truncated form (HDAC4+C) like that produced by the human mutant gene, which lacks the deacetylase domain and the nuclear export signal, was retained in the nucleus of neurons, was bound to chromatin, and repressed gene expression. Knockdown of HDAC4 in neuronal cultures caused neuronal death, which was rescued by expression of forms of HDAC4 that were constitutively cytosolic but not by constitutively nuclear mutants. Expression of constitutively nuclear mutants (HDAC4-3SA and HDAC4+C) inhibited synaptic activity (based on electrophysiological analysis) and reduced the sizes of the docked vesicle pools and length of the presynaptic active zones and the postsynaptic densities (as indicated by electron microscopy). Transgenic mice expressing the HDAC4+C form exhibited decreased synaptic activity by electrophysiological analysis of slice preparations and impaired spatial learning and memory in behavior tests. Thus, HDAC4 appears to serve as an inhibitor of synaptic activity by functioning as a transcriptional repressor that is excluded from the nucleus in response to activity-dependent phosphorylation.

R. Sando III, N. Gounko, S. Pieraut, L. Liao, J. Yates III, A. Maximov, HDAC4 governs a transcriptional program essential for synaptic plasticity and memory. Cell 151, 821–834 (2012). [Online Journal]

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