This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. While the involvement of NMDA receptors in postnatal activity-dependent plasticity is well established, less is understood about the function of non-NMDA receptors in this process. In motor neurons, the AMPA GluR1 subunit is expressed during development, but is downregulated when neurons have attained their mature phenotype. Previous experiments have shown that overexpression of GluR1 in motor neurons at the end of their development results in an increased number of dendrite branch-points, suggesting that some aspects of dendrite plasticity are controlled by AMPA receptor expression in these neurons. This proposal will use real-time imaging of mammalian spinal cord cultures and cortical cultures transfected with individual AMPA receptor subunits, to measure dynamic rates of dendrite reorganization. The precise developmental role of subunits which constitute calcium-permeable and calcium-impermeable AMPA receptors will be investigated using transfection of bicistronic vectors. Quantitative PCR will be used to establish the temporal pattern of AMPA receptor expression in developing neurons. Further, temporally restricted knock-down of individual AMPA receptors using RNAi will investigate whether developmental regulation of AMPA receptors limits morphological plasticity of dendrites. Experiments will investigate whether neuronal activity itself regulates expression of specific AMPA receptor subunits. Studies in cultured neurons will be complemented with observations drawn from in vivo models which employ targeted knockout of AMPA receptor subunits and their intracellular signaling molecules, and from models of locomotor and postural dysfunction. Determining how AMPA receptors govern specific features of dendritic plasticity is fundamental in comprehending how functional connectivity may be modulated during neuronal development.
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