NR3A and NR3B represent a newly identified family of JV-methyl-D-aspartate receptor (NMDAR) subunits. In Project HI, we will investigate NR3A/3B function at the whole animal/systems level. Our previous data indicate that rodogenous NR3 may act as a dominant-interfering molecule of classical NMDAR activity (classical NMDAR refers to receptors composed of NR1/NR2 subunits). Additionally, NR3A/3B can form excitatory glycine-sensitive channels (not responsive to glutamate) in recombinant systems when co-expressed with NR1 in the absence of NR2 subunits. NMDARs are thought to play crucial roles in both normal development and neurotoxicity mediated by glutamate (excitotoxicity). Excitotoxicity has been implicated in neuronal injury and death in focal cerebral hypoxia/ischemia as well as a number of neurodegenerative disorders. The elucidation of the role of NR3A/3B in these events requires animal models. Toward this goal, we have generated four different mutant mice in this project: knockout (KO) mice of NR3A and NR3B, and transgenic (Tg) mice for NR3A and NR3B. Our preliminary studies show that NR3A KO mice exhibit phenotypic changes, including morphological changes (enhanced dendritic spine size and number), electrophysiological alterations (faster rise time of the NMDAR component of the excitatory postsynaptic current [EPSC]), and behavioral modifications. Here, NR3 KO and Tg mice will be subjected to further electrophysiological studies and pathophysiologically relevant experiments to test for in vivo modulation of NMDAR activity by NR3 during neonatal development. In related experiments, this Project identified a gene that is upregulated in NR3A KO mice. The gene, named p!6 based on its predicted MW, is a member of a novel and large gene family. Forced expression of p!6 in hippocampal neurons increases NMDAR activity, the number of PSD-95 punctae, and the number of dendritic spines. Hence, p!6 may be involved in the manifestation of the altered phenotype of NR3A KO mice.
The Specific Aims of Project III are ? 1. To examine properties of synaptic transmission and plasticity (long-term potentiation [LTP] and long-term depression [LTD]) in slice preparations from NR3A/3B KO and Tg mice. 2. To examine neuronal damage in vivo following hypoxia/ischemia in NR3A KO and NR3A/3B Tg mice. 3. To examine molecular, functional, and structural properties of p!6, the product of a novel gene family that is upregulated in NR3A KO mice.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sanford-Burnham Medical Research Institute
La Jolla
United States
Zip Code
Tu, Shichun; Akhtar, Mohd Waseem; Escorihuela, Rosa Maria et al. (2017) NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism. Nat Commun 8:1488
Chen, Shanyan; Cui, Jiankun; Jiang, Tao et al. (2017) Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke. J Cereb Blood Flow Metab 37:188-200
Nagar, Saumya; Trudler, Dorit; McKercher, Scott R et al. (2017) Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency. Invest Ophthalmol Vis Sci 58:3741-3749
Nakamura, Tomohiro; Lipton, Stuart A (2017) 'SNO'-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders. Trends Endocrinol Metab 28:879-892
Nagar, Saumya; Noveral, Sarah M; Trudler, Dorit et al. (2017) MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress. Proc Natl Acad Sci U S A 114:E4048-E4056
Mann, Aman P; Scodeller, Pablo; Hussain, Sazid et al. (2017) Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer's disease. Nat Commun 8:1403
Satoh, Takumi; Lipton, Stuart (2017) Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate. F1000Res 6:2138
Nakamura, Tomohiro; Lipton, Stuart A (2016) Nitrosative Stress in the Nervous System: Guidelines for Designing Experimental Strategies to Study Protein S-Nitrosylation. Neurochem Res 41:510-4
Nakamura, Tomohiro; Lipton, Stuart A (2016) Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases. Trends Pharmacol Sci 37:73-84
Lipton, Stuart A; Rezaie, Tayebeh; Nutter, Anthony et al. (2016) Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer's disease models. Cell Death Dis 7:e2499

Showing the most recent 10 out of 173 publications