This is a proposal for renewal of RO1 MH053608 that examines the immediate early gene Arc, its role in activity- dependent synaptic plasticity, and its contribution to diseases that impact mental health. Our plans focus on a novel function of Arc that mediates AKT signaling down-stream of the NMDA receptor. This mechanism is distinct from canonical functions of Arc that mediate synaptic scaling and long-term depression. Preliminary studies suggest that NMDAR-Arc-AKT signaling stabilizes NMDAR expression at the membrane and may contribute to metaplastic synaptic potentiation. NMDAR, Arc and AKT are each suspected hubs for schizophrenia, and proposed studies seek to understand both the natural function of NMDAR-Arc-AKT signaling and how disruption of this pathway may contribute to schizophrenia.
Aim 1 examines the protein composition, assembly, NMDA receptor pharmacology, synapse specificity of the signaling pathway, and its role in synaptic plasticity.
Aim 2 examines NMDAR-Arc-AKT signaling in vivo and examines its hypothesized role to potentiate D1 receptor signaling, its role in the establishment of behaviorally linked ensembles of excitatory neurons, and to discover adaptions to disruption of the pathway that cause hyperdopaminergic signaling.
Aim 3 tests the prediction that NMDAR-Arc-AKT signaling is important for adaptation to stress that can induce schizophrenia-like endophenotypes in vulnerable animals, and examines a hypothetical mechanism that is based on human and mouse studies suggesting failure of interneuron mechanisms.
Aim 4 will examine the NMDAR-Arc-AKT complex and signaling in human brain and iPS neurons in collaboration with the Lieber Institute for Brain Development. Studies will create and compare protein and RNAseq biomarkers from mouse models representing failure of NMDAR-Arc-AKT complex formation and signaling, and compare these with best available databases from human subjects with well characterized genetic load for schizophrenia. Our hope is to confirm a role for the NMDAR-Arc-AKT pathway as a basis for risk in polygenetic human disease.

Public Health Relevance

Our studies focus on the molecular basis of memory consolidation and the particular role of a gene termed Arc. We have discovered a new signaling pathway mediated by Arc that appears important for memory and for understanding schizophrenia. Studies will reveal the molecular basis of Arc signaling, its contribution to normal memory, and the impact of its dysfunction in relation to schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Driscoll, Jamie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 17 publications