Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription

Abstract

The formation of new memories requires transcription. However, the mechanisms that limit signaling of relevant gene programs in space and time for precision of information coding remain poorly understood. We found that, during learning, the cellular patterns of expression of early response genes (ERGs) are regulated by class IIa HDACs 4 and 5, transcriptional repressors that transiently enter neuronal nuclei from cytoplasm after sensory input. Mice lacking these repressors in the forebrain have abnormally broad experience-dependent expression of ERGs, altered synaptic architecture and function, elevated anxiety, and severely impaired memory. By acutely manipulating the nuclear activity of class IIa HDACs in behaving animals using a chemical-genetic technique, we further demonstrate that rapid induction of transcriptional programs is critical for memory acquisition but these programs may become dispensable when a stable memory is formed. These results provide new insights into the molecular basis of memory storage.

Epigenetic Regulation as a Basis for Long-Term Changes in the Nervous System: In Search of Specificity Mechanisms

“…It seems that the level of neuron excitability influences the HDAC4/5 distribution between the nucleus and cytoplasm and determines what cells will be allocated into the functional network more effectively. This hypothesis was confirmed by the work of Zhu et al [59] in which the HDAC4 distribution was ana lyzed immunohistochemically in the nuclei of neurons after learning. General increase in the HDAC4 content was shown in the nuclei of neurons, however, this was not the case for the potential engram cells, where the authors observed a very weak overlapping between the Fos posi tive cells (marker of the engram neurons) and nuclear HDAC4.…”

“…It was demonstrated that the balance shift towards the excessive content of HDAC IIa in the nucleus (under condition of overexpression of the phosphorylation resistant mutant isoform) was accompanied by the stimu lus dependent suppression of transcription of a number of the plasticity related genes (Homer1, Arc, Npas4, Nr4a1, Egr2, etc.) [59,61].…”

“…According to some data, the nuclear cytoplasmic translocations of HDAC4/5 can play an important role in the formation of engrams and memory encoding [59]. Normally the engram size is fixed and allocation of the cells into the limited functional network is accompanied by a certain selection of neurons based, at least, on their excitability characteristics (regulating the activation level) during learning [62].…”

Environmental Stimulation Counteracts the Suppressive Effects of Maternal High-Fructose Diet on Cell Proliferation and Neuronal Differentiation in the Dentate Gyrus of Adult Female Offspring via Histone Deacetylase 4

“…Maternal diet is a critical modulator of offspring epigenetics [47]. HDCA4 is one member of class II HDACs which negatively regulates learning and memory by gene repression [48]. A previous study demonstrated that enhanced HDAC4 mediated the maternal HFD-induced suppression of hippocampal BDNF [6].…”

Mechanisms that communicate features of neuronal activity to the genome

“…This suppression is decoupled following depolarization, permitting transcription of the NCoR2 bound genes [27 ]. An additional mechanism for dynamic repression of activity-regulated genes is observed with the Class II HDACs which translocate to the nucleus in response to stimuli and repress depolarization induced genes, including Npas4 [28,29]. The interaction between repressors and activators is by definition a competition; the absolute number of activating and repressing proteins in the nucleus can sway the outcome of this competition.…”