The acquisition of mature neuronal structure and connectivity depend on synaptic activity during a brief period in early postnatal life. What molecular determinants endow neonatal but not adult neurons with the susceptibility to such developmental activity-dependent plasticity? One determinant appears to be the glutamate receptor subunit GluR1. Neonatal motor neurons are known to express GluR1 abundantly while adults are largely devoid of GluR1. We found expressing GluR1 in motor neurons outside the critical period (using viral vectors) leads to dramatic remodeling of dendritic architecture. To determine if the expression of GluR1 in neonatal motor neurons is important for the normal elaboration of dendrites, we will study mice with a null mutation in GluR1 (specific aim 1). The electrophysiological properties of glutamate receptors containing GluR1 that foster dendrite remodeling will be explored in specific aim 2. This will be accomplished with mutant forms of GluR1 and for comparison, analogous mutants in another subunit GluR2. In addition to the glutamate receptor phenotype of motor neurons, another factor that appears to control dendritic growth during the critical period is nitric oxide (NO). We found that the dendritic tree of developing motor neurons in nNOS knock-out animals is smaller and less branched than wildtype animals.
In specific aim 3, we will express nNOS in the spinal cord (using viral vectors) to more directly implicate NO signaling in dendritogenesis. The similar effects of GluR1 and NO on dendrites suggest a common molecular mechanism may be involved. NO is known to stimulate calcium/calmodulin kinase II (CamKII) and GluR1 is phosphorylated by CamKII. To begin to study a possible link between NO and GluR1 in the developing spinal cord, we will examine the development of dendrites in the CamKII knock-out animals (specific aim 4). If the normal elaboration of the dendritic tree is perturbed, the stage will be set for ordering the molecules we have identified in a pathway that begins with synaptic activity and leads to dendritic growth. Activity-dependent development solves the task of establishing precise connections and application of this form of plasticity may have therapeutic potential for the remodeling brain about insults. These proposed studies aim to uncover the molecular mechanisms subserving the activity-dependent acquisition of mature neuronal phenotype.
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