The goal of this project is to elucidate the molecular mechanisms of experience-dependent plasticity of neural circuits essential for learning and memory. We focus on class IIa histone deacetylases (HDACs), transcriptional repressors that shuttle between the nucleus and cytoplasm. We and our colleagues have previously demonstrated that the class IIa HDAC isoform, HDAC4, regulates memory in mice, drosophila and C.elegans. In conjunction with these findings, HDAC4 has been linked to several neurological disorders in humans. In the initial project period, we discovered that HDAC4 and its close homolog, HDAC5, restrict the transcriptional response to sensory input. These observations support the hypothesis that plasticity- and memory-related genes are dynamically repressed in the brain in any environment. Here, we propose to determine how class IIa HDACs operate at circuit, cellular and molecular levels, and how their nuclear signaling impacts neurons in the mouse hippocampus. Moreover, we will exploit class II HDACs as tools for rapid chemical-genetic control of transcription in behaving animals.
Our aims are: 1) To determine how class IIa HDAC operate at a circuit level by using immunofluorescent microscopy, activity-based tagging of memory engrams cells, and in vivo 2-photon imaging of repressors and calcium indicators; 2) To identify nuclear effectors of class IIa HDACs in specific genetically-defined neuron types by deep sequencing and mass spectrometry; 3) To define the consequences of class IIa HDACs signaling on circuit structure and function. This will be accomplished by combining electron microscopy, whole-brain imaging, and electrophysiology; and 4) To leverage chemical-genetic manipulation of class IIa HDAC signaling for mapping of brain areas where activity-dependent transcription promotes memory coding. Taken together, these studies will explain how neuronal chromatin-binding proteins associated with human disease function in the normal brain, and will provide novel insights into the basic mechanisms underlying network plasticity and memory storage.
Our proposal aims to investigate the molecular mechanisms of transcriptional control of neuronal plasticity and memory storage. This basic research will provide new and significant insights into the function of normal brain, and will facilitate the development of new effective treatments of neurological disorders.
| Sando, Richard; Bushong, Eric; Zhu, Yongchuan et al. (2017) Assembly of Excitatory Synapses in the Absence of Glutamatergic Neurotransmission. Neuron 94:312-321.e3 |
| Lobanova, Anastasia; She, Robert; Pieraut, Simon et al. (2017) Different requirements of functional telomeres in neural stem cells and terminally differentiated neurons. Genes Dev 31:639-647 |
| Kwon, Seok-Kyu; Sando 3rd, Richard; Lewis, Tommy L et al. (2016) LKB1 Regulates Mitochondria-Dependent Presynaptic Calcium Clearance and Neurotransmitter Release Properties at Excitatory Synapses along Cortical Axons. PLoS Biol 14:e1002516 |
| Shimojo, Masafumi; Courchet, Julien; Pieraut, Simon et al. (2015) SNAREs Controlling Vesicular Release of BDNF and Development of Callosal Axons. Cell Rep 11:1054-66 |
| Pieraut, Simon; Gounko, Natalia; Sando 3rd, Richard et al. (2014) Experience-dependent remodeling of basket cell networks in the dentate gyrus. Neuron 84:107-122 |
