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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
3P01HD029587-16S2
Application #
8231886
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
2009-09-01
Project End
2011-11-30
Budget Start
2009-09-01
Budget End
2011-11-30
Support Year
16
Fiscal Year
2011
Total Cost
$85,862
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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