Glutamate toxicity, both direct and indirect, has been proposed to be a major factor contributing to motor neuron diseases. Glutamate toxicity is mediated by abnormal activation of ionotropic glutamate receptors of both the NMDA and non-NMDA receptor gene families. We have recently cloned a new member of the NMDA receptor (NMDAR) family, tentatively designated NR3B, which is expressed almost exclusively in motor neurons. Remarkably, when co-expressed in oocytes with NR1 and/or NR2A subunits, NR3B dramatically alters the ligand specificity and ion permeability of the NMDAR, as well as its sensitivity to channel blockers. Based on the unique electrophysiological properties and expression pattern of this new subunit, we hypothesize that the NR3B subunit may play a central role in motor neuron function, for example, in maintaining intracellular calcium homeostasis, and may explain the observed differences in NMDAR pharmacology in spinal cord versus brain. Furthermore, we propose that a disruption in the normal expression, localization, or processing of the NR3B subunit could contribute to specific degeneration of motor neurons, such as that observed in amyotrophic lateral sclerosis (ALS) and/or other motor neuron diseases. The following studies will be carried out to test these hypotheses:
Specific Aim 1. The mechanism by which NR3B subunit expression alters NMDA receptor function will be delineated. To do this, the molecular profile and functional properties of NMDA receptors in motor neurons of the spinal cord will be characterized. In particular, we will evaluate the degree to which changes in NR3B expression level and/or subcellular localization during development and aging affect NMDAR function.
Specific Aim 3. An NR3B-null mouse strain will be generated and evaluated for possible pathological changes in motor neurons. The long-term goals include the development of an NR3B-related mouse model for motor neuron degenerative diseases.
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| Xing, Guo-Gang; Wang, Rengang; Yang, Bo et al. (2006) Postnatal switching of NMDA receptor subunits from NR2B to NR2A in rat facial motor neurons. Eur J Neurosci 24:2987-92 |
