Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological histone deacetylase (HDAC) inhibitors, primarily those targeted to Class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of Class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual Class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.
Histone acetylation and deacetylation can be dynamically regulated in response to environmental stimuli and play important roles in learning and memory. Pharmacological inhibition of histone deacetylases (HDACs) improves performance in learning tasks, however these classical agents are ‘pan-HDAC’ inhibitors and their use makes it difficult to determine the roles of specific HDACs in cognitive function. We took a genetic approach using mice lacking the class I HDACs, HDAC1 or HDAC2, in postmitotic forebrain neurons to investigate the specificity or functional redundancy of these HDACs in learning and synaptic plasticity. We show that selective knockout of HDAC2 led to a robust acceleration of the extinction rate of conditioned fear responses and a conditioned taste aversion as well as enhanced performance in an attentional set-shifting task. HDAC2 knockout had no impact on episodic memory or motor learning suggesting that the effects are task-dependent, with the predominant impact of HDAC2 inhibition being an enhancement in an animal’s ability to rapidly adapt its behavioral strategy as a result of changes in associative contingencies. Our results demonstrate that the loss of HDAC2 improves associative learning, with no effect in non-associative learning tasks, suggesting a specific role for HDAC2 in particular types of learning. HDAC2 may be an intriguing target for cognitive and psychiatric disorders that are characterized by an inability to inhibit behavioral responsiveness to maladaptive or no longer relevant associations.
Rett syndrome and MECP2 duplication syndrome are neurodevelopmental disorders that arise from loss of function and gain of function alterations in Methyl-CpG Binding Protein 2 (MeCP2) expression, respectively. Although there have been studies examining MeCP2 loss of function in animal models, there is limited information on MeCP2 overexpression in animal models. Here, we characterize a mouse line with MeCP2 overexpression restricted to neurons (Tau-Mecp2). This MeCP2 overexpression line shows motor coordination deficits, heightened anxiety, and impairments in learning and memory that are accompanied by deficits in long-term potentiation and short-term synaptic plasticity. Whole cell voltage clamp recordings of cultured hippocampal neurons from Tau-Mecp2 mice reveal augmented frequency of miniature excitatory postsynaptic currents with no change in miniature inhibitory postsynaptic currents indicating that overexpression of MeCP2 selectively impacts excitatory synapse function. Moreover, we show that alterations in transcriptional repression mechanisms underlie the synaptic phenotypes in hippocampal neurons from the Tau-Mecp2 mice. These results demonstrate the Tau-Mecp2 mouse line recapitulates many key phenotypes of MECP2 duplication syndrome and support the use of these mice to further study this devastating disorder.
Psychiatric disorders including major depressive disorder, drug addiction, and schizophrenia are debilitating illnesses with a multitude of complex symptoms underlying each of these disorders. In recent years, it has become appreciated that the onset and development of these disorders goes beyond the one gene-one disease approach. Rather, the involvement of many genes is likely linked to these illnesses, and regulating the activation or silencing of gene function may play a crucial role in contributing to their pathophysiology. Epigenetic modifications such as histone acetylation and deacetylation, as well as DNA methylation can induce lasting and stable changes in gene expression, and have therefore been implicated in promoting the adaptive behavioral and neuronal changes that accompany each of these illnesses. In this review we will discuss some of the latest work implicating a potential role for epigenetics in psychiatric disorders, namely, depression, addiction, and schizophrenia as well as a possible role in treatment.
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