The unifying theme of this revised P01 Grant renewal is a cellular and molecular approach to intellectual and developmental disabilities in an attempt to uncover processes contributing to neuronal synaptic damage, particularly in Down syndrome (DS). Three inter-related projects are planned. They all study overstimulation of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR), leading to synaptic damage and cognitive dysfunction in children. Here we show that oligomers of AP protein, as found in DS with or without Alzheimer's disease, can trigger excessive stimulation of extrasynaptic NMDARs, contributing to loss of thin dendritic spines, with resulting compromise of synaptic function and cognitive ability. This P01 Grant is credited with developing the first clinically-tolerated NMDAR antagonist, Memantine, which we showed is an uncompetitive, open-channel blocker with a relatively fast off-rate, accounting for its clinical tolerability. We then developed new, more effective drugs, called NitroMemantines, for the treatment of neonatal hypoxic- ischemic brain damage. NitroMemantines act on NMDAR channels (like Memantine) but also donate NO species to react at nitrosylation sites on the NMDAR to further downregulate excessive activity better than Memantine. Additionally, we plan to develop novel drugs based on structure-function relationships of the NR3 family of NMDAR subunits, which were discovered under the auspices of this PO1 grant. Project I will study the basis of NitroMemantine action and develop new NMDAR antagonists based on NR3 structure- function. Project II will test NitroMemantine vs. Memantine to prevent synaptic damage and cognitive deficits in DS using human fetal and IPS cell-based models in culture and the mouse Ts65Dn model in vivo. Project III will complement Project II by taking a genetic rather than a pharmacologic approach to downregulating excessive NMDAR activity or its downstream effects. Accordingly, Project III will test genetic models of altered NR3 genes or the downstream takusan family of genes for neuroprotection in similar in vitro and in vivo models of DS as in Project 11. The CORE supports administration, statistics, tissue culture, and crystallography/modeling of NMDAR subunits and functional sites, all critical to the proposed Projects.

Public Health Relevance

This grant aims to develop novel, clinically-tolerated NMDA receptor antagonists, called NitroMemantines, in addition to other novel molecules based on the structure of NRS subunits, which this Team of Investigators discovered, in order to prevent cognitive deficits seen in Down syndrome. To do this, we take two approaches, pharmacological and genetic, and use electrophysiological, histological, and behavioral analyses.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-N (51))
Program Officer
Oster-Granite, Mary Lou
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
Akhtar, Mohd Waseem; Sanz-Blasco, Sara; Dolatabadi, Nima et al. (2016) Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation. Nat Commun 7:10242
Nakamura, Tomohiro; Lipton, Stuart A (2016) Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases. Trends Pharmacol Sci 37:73-84
Nakanishi, Nobuki; Kang, Yeon-Joo; Tu, Shichun et al. (2016) Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model. J Mol Neurosci 58:59-65
Sanz-Blasco, Sara; Piña-Crespo, Juan C; Zhang, Xiaofei et al. (2016) Levetiracetam inhibits oligomeric Aβ-induced glutamate release from human astrocytes. Neuroreport 27:705-9
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
Sunico, Carmen R; Sultan, Abdullah; Nakamura, Tomohiro et al. (2016) Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons. Proc Natl Acad Sci U S A 113:E7564-E7571
Nakamura, Tomohiro; Prikhodko, Olga A; Pirie, Elaine et al. (2015) Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. Neurobiol Dis 84:99-108
Satoh, Takumi; Stalder, Romain; McKercher, Scott R et al. (2015) Nrf2 and HSF-1 Pathway Activation via Hydroquinone-Based Proelectrophilic Small Molecules is Regulated by Electrochemical Oxidation Potential. ASN Neuro 7:
Galluzzi, L; Bravo-San Pedro, J M; Vitale, I et al. (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 22:58-73
Zhang, Dongxian; Lee, Brian; Nutter, Anthony et al. (2015) Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid. J Neurochem 133:898-908

Showing the most recent 10 out of 162 publications