This application is a competitive renewal of R01 MH 53608-09. The focus of the proposal is to examine the function of the immediate early gene (lEG) termed Arc, and its contribution to activity-dependent plasticity. Arc was cloned in our laboratory based on its rapid induction in response to neuronal activity (Lyford, 1995). Arc mRNA is strikingly induced during learning behaviors and its transcriptional response provides the basis for a novel imaging method that detects stable neural networks in brain (Guzowski, 1999). Arc protein appears to be essential for learning and memory as interruption of Arc induction blocks the maintenance phase of LTP and disrupts memory (Guzowski, 2000). These studies focus attention on the molecular basis of Arc protein function at the synapse. In preliminary studies for the present renewal, we find that Arc protein interacts with certain SH3 domain proteins and also interacts with CaMKII. Moreover, Arc expression induces a LTD-like down regulation of AMPAR responses in hippocampal neurons.
Aim 1 will examine the hypothesis that Arc functions to recruit the SH3 domain protein termed endophilin 3, together with CaMKII, to form a unique endocytic vesicle that is involved in AMPAR trafficking. Biochemical studies will define the composition of the putative Arc endosome, and structural determinants of Arc essential for its action.
Aim 2 will examine the mechanism of Arc function at the excitatory synapse. Preliminary studies indicate that the SH3 interaction site of Arc is required to evoke down regulate AMPAR, and proposed studies will test the hypothesis that the Arc-endosome selectively modifies trafficking of distinct AMPAR. We will also examine mechanisms that regulate localized expression of Arc protein.
Aim 3 will generate mouse transgenic models to test the contribution of the SH3 and CaMKII interaction domains of Arc on synaptic and behavioral plasticity. These studies will identify novel mechanisms that underlie long-term, activity-dependent neuronal plasticity, and explore promising links with the biology of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH053608-13
Application #
7170052
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Asanuma, Chiiko
Project Start
1994-09-30
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
13
Fiscal Year
2007
Total Cost
$348,813
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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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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