The Regulation of Hippocampal Synaptic Plasticity by Upstream and Downstream Effectors of Histone Acetylation
Neuroscience and Neurobiology
Long-lasting forms of hippocampal plasticity and hippocampus-dependent memory share a requirement for gene expression. Activity-induced neuronal gene expression is regulated by epigenetic mechanisms such as the post-translational modification of histone proteins. Histone acetylation plays a major role in neuronal function, but our understanding of the upstream mechanisms that regulate recruitment of the HDAC enzymes, and of the genes and proteins downstream of histone acetylation that support plasticity, are poorly understood. In my thesis research I investigated the role of the SIN3A/HDAC complex, a repressive histone-modifying complex, and of the Nr4a nuclear receptors, which are acetylation-regulated and memory-related transcription factors, in hippocampal synaptic plasticity. In Chapter 1, I discussed the mechanisms that support memory formation and the stabilization of synaptic potentiation, described the mechanisms of post-translational histone modification, and reviewed the role of epigenetic histone modification in memory and plasticity as well as in neuronal dysfunction. In Chapter 2, we demonstrated that reducing levels of the co-repressor SIN3A enhanced long-term potentiation and long-term memory, increased expression of Cdk5 and Homer1, and altered signaling through the Group I metabotropic glutamate receptors. In the Appendix, I show additional data that demonstrates increased mGluR5-mediated signaling in hippocampal neurons with loss of SIN3A. In Chapter 3, I found that disrupting the function of the Nr4a family of nuclear receptor transcription factors impaired long-lasting forms of synaptic potentiation and blocked the enhancement of plasticity by pharmacological HDAC inhibition. In Chapter 4 I found that C-DIM compounds, activators of NR4A, enhanced hippocampal potentiation in a manner sensitive to Nr4a disruption; we also found that CREB/CBP interaction regulates activity-induced Nr4a2 promoter acetylation and gene expression. These findings improve our understanding of the role of epigenetic histone modification in synaptic plasticity and memory, and indicate that the NR4A nuclear receptors are exceptional downstream targets for the enhancement of cognitive function and the amelioration of neuronal dysfunction.