Abstract
Long-term memory depends on the control of activity-dependent neuronal gene expression, which is regulated by epigenetic modifications. The epigenetic modification of histones is orchestrated by the opposing activities of 2 classes of regulatory complexes: permissive coactivators and silencing corepressors. Much work has focused on coactivator complexes, but little is known about the corepressor complexes that suppress the expression of plasticity-related genes. Here, we define a critical role for the corepressor SIN3A in memory and synaptic plasticity, showing that postnatal neuronal deletion of Sin3a enhances hippocampal long-term potentiation and long-term contextual fear memory. SIN3A regulates the expression of genes encoding proteins in the postsynaptic density. Loss of SIN3A increases expression of the synaptic scaffold Homer1, alters the metabotropic glutamate receptor 1α (mGluR1α) and mGluR5 dependence of long-term potentiation, and increases activation of ERK in the hippocampus after learning. Our studies define a critical role for corepressors in modulating neural plasticity and memory consolidation and reveal that Homer1/mGluR signaling pathways may be central molecular mechanisms for memory enhancement.
Highlights
Long-term memory consolidation and hippocampal long-term potentiation (LTP) depend on activity-dependent neuronal gene expression, which is, in turn, regulated by epigenetic mechanisms such as posttranslational histone modifications (1, 2)
Given the enhancement in hippocampal LTP by Sin3a deletion, we investigated the ability of an histone deacetylase (HDAC) inhibitor to further enhance LTP in Sin3a neuronal hypomorphs (Sin3aNH) mice
Homer1 and Cdk5 are implicated in memory consolidation, and both proteins function in a common pathway regulating the localization and function of type I metabotropic glutamate receptors (mGluRs), so we further investigated the role of HOMER1 and mGluR signaling in Sin3aNH animals (4, 28)
Summary
Long-term memory consolidation and hippocampal long-term potentiation (LTP) depend on activity-dependent neuronal gene expression, which is, in turn, regulated by epigenetic mechanisms such as posttranslational histone modifications (1, 2). Histone acetylation is associated with transcriptional activation, and both histone acetylation and expression of acetylation-regulated genes are increased during memory consolidation (1, 3–5). Acetylation levels are determined by the activity of histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes, which are recruited to chromatin by association with coactivator and corepressor proteins (6–8). HATs such as CBP and p300 are recruited by the transcription factor and coactivator protein CREB in response to signaling cascades triggered by synaptic activity (9). Corepressors have been linked to dynamic and activity-dependent regulation of gene expression, and neuron-specific components of corepressor complexes have been described (12), suggesting that these proteins are important in regulating transcription-dependent plasticity. Few studies have directly addressed the function of the corepressor proteins in memory and plasticity
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