Mechanisms of AMPA receptor-mediated activity-dependent development

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Synaptic activity sculpts the architecture of neurons and their connections within circuits during development to establish the final structural and electrical properties of the mature central nervous system,5. This occurs throughout the neuraxis including the spinal cord where activity of GluA-1 containing AMPA receptors (AMPA-R) is translated into a pro-dendrite growth signal during early postnatal life41,43. The precise molecular mechanism by which this occurs is incompletely understood. This process is important because neurons with different dendritic trees are distinctive in the way they receive, compute, and transmit information5. In this proposal, I focus on the mechanism by which the GluA1 subunit of AMPA-R translates synaptic activity into dendrite growth and branching in the spinal cord. Prior work indicates that the GluA1 subunit is critical in activity-dependent development of the spinal cord in a manner that is independent of NMDA receptors (NMDA-R)41. In the spinal cord, endogenous high expression of GluA1 in early life is essential for the proper elaboration of motor neuron dendrites, the specific patterns of pre-synaptic input onto motor neurons, and the emergence of normal locomotor behavior41. This property of GluA1 is dependent on its endogenous, physical interaction with SAP97 (synapse-associated protein of 97 kDa molecular weight)43. Recent unpublished work indicates that the pro-dendrite growth activity of the GluA1/SAP97 is dependent on the PDZ3 domain of SAP97; without a functional PDZ3 binding domain, these pro-dendrite growth properties of GluA1 and SAP97 are completely lost. I have furthermore identified CRIPT (cysteine-rich interactor of PDZ-three) as an endogenous and specific binding partner of the PDZ3 domain of SAP97 and observed that overexpression of CRIPT increases dendritic length and branching in vitro. I thereby hypothesize that GluA1 and SAP97 form a multi-protein complex with CRIPT at the cell surface either at, or near, synapses whereby GluA1-containing AMPA-R use SAP97/CRIPT to translate AMPA-R activity into dendritic growth and branching in the spinal cord. ) PUBLIC HEALTH RELEVANCE: By completing this work, I hope to gain mechanistic insight into AMPA-R-mediated activity-dependent development of motor neuron dendrites in the spinal cord, a form of plasticity that is NMDA-R independent. Insult to the CNS often leads to a deterioration of connections within the affected neuronal circuit. Harnessing AMPA-R-mediated plasticity in the spinal cord may therefore have therapeutic applications by promoting reformation of those connections3. )