This is a proposal to renew RO1 MH053608, which supports our studies of the immediate early gene Arc. Arc is a synaptic protein that is required for animals to learn and store information1. Arc associates with endocytic proteins to regulate glutamate receptor trafficking and thereby control the strength of excitatory synapses2,3. Arc-dependent mechanisms play an important role in synaptic plasticity of learning, but are also implicated in diseases of cognition including fragile X mental retardation syndrome4-6, Angelman syndrome7, Alzheimer's disease8,9 and schizophrenia 10,11. The association of Arc with synaptic pathophysiology drives a need for deep understanding of Arc's function. This has been challenging because Arc is a single copy gene without discernable family members or recognizable functional domains. To address this challenge, we have focused recent efforts on defining the structure of Arc, and have made break through discoveries that reveal the basis of Arc association with synaptic proteins important for trafficking and synaptic turnover. We have also identified protein interactions that support a role for Arc in control of PI3 Kinase, AKT and mTORC. Studies will evaluate hypotheses of Arc functions that derive from new structural information and that are central to its action in synaptic plasticity and disease.
Arc is a protein that functions to control the strength of excitatory synapses and is implicated in several diseases of cognition as a mediator of synaptic weakening and failure. Proposed studies will reveal the structural basis of Arc's function and will test a model of its contribution to cognitive disease. Studies will also explore the potential of nw targets for therapeutics.
|Smith-Hicks, Constance L; Cai, Peiling; Savonenko, Alena V et al. (2017) Increased Sparsity of Hippocampal CA1 Neuronal Ensembles in a Mouse Model of Down Syndrome Assayed by Arc Expression. Front Neural Circuits 11:6|
|Husain, Nilofer; Yuan, Qiang; Yen, Yi-Chun et al. (2017) TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation. Aging Cell 16:281-292|
|Bilkey, David K; Cheyne, Kirsten R; Eckert, Michael J et al. (2017) Exposure to complex environments results in more sparse representations of space in the hippocampus. Hippocampus 27:1178-1191|
|Na, Youn; Park, Sungjin; Lee, Changhee et al. (2016) Real-Time Imaging Reveals Properties of Glutamate-Induced Arc/Arg 3.1 Translation in Neuronal Dendrites. Neuron 91:561-73|
|Zhang, Wenchi; Wu, Jing; Ward, Matthew D et al. (2015) Structural basis of arc binding to synaptic proteins: implications for cognitive disease. Neuron 86:490-500|
|Okuno, Hiroyuki; Akashi, Kaori; Ishii, Yuichiro et al. (2012) Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKII?. Cell 149:886-98|
|Wu, Jing; Petralia, Ronald S; Kurushima, Hideaki et al. (2011) Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent ?-amyloid generation. Cell 147:615-28|
|Zou, Jia; Zhou, Liang; Du, Xiao-Xia et al. (2011) Rheb1 is required for mTORC1 and myelination in postnatal brain development. Dev Cell 20:97-108|
|Alberi, Lavinia; Liu, Shuxi; Wang, Yue et al. (2011) Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks. Neuron 69:437-44|
|Greer, Paul L; Hanayama, Rikinari; Bloodgood, Brenda L et al. (2010) The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140:704-16|
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