Throughout the neuroaxis, excitatory neurotransmission within the neonatal CNS provides the permissive substrate and/or instructs the formation of precisely patterned axonal and dendritic arbors with specific synaptic connections. The restriction of this process to early postnatal life is likely to be due to the unique molecular composition of neonatal neurons. We hypothesize that glutamate receptor phenotype of neurons plays a central role in controlling their activity-dependent plasticity both during development and in maturity. In support of this we have found that during the time when they elaborate their dendritic tree, spinal motor neurons express very high levels of the GluRt subunit of the AMPA subtype of glutamate receptor. If neonatal motor neurons do not express GluR1 or express a version of GluR1 in which the C terminal 7 amino acids are deleted (GluR1 delta?), their dendritic tree do not develop normally. If mature motor neurons are forced to express GluR1, they extensively remodel their dendritic trees. In the 1st specific aim we will characterize the motor behavior and intra-segmental spinal cord connectivity in the GluR1 knock-out and GluR1delta7-expressing mice.
In specific aim 2 we investigate the role of SAP97 (a PDZ-domain containing protein known to bind the C-terminus of GluR1) in motor neuron dendrite growth.
In specific aim 3, we will create a transgenic mouse that expresses GluR1 in mature motor neurons and then determine the effect this has on locomotor behavior, spinal cord circuitry and spinal learning in a spinal cord injury paradigm. Exploring the molecular mechanism by which activity-dependent processes fine-tune neuronal architecture and interneuronal connectivity may enable us harness this form of plasticity to promote useful remodeling of CNS structures after insults.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Refolo, Lorenzo
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Children's Hospital of Philadelphia
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