The targeted delivery of AMPA-type glutamate receptors (AMPAR) from intracellular compartments to the postsynaptic membrane is a major cellular mechanism for learning-related synaptic plasticity in the mammalian brain. Yet, little is known about the molecular machinery that ensures the spine- specific transport of AMPARs to the synapse. Prior work in our laboratory has demonstrated that recycling endosomes (REs) within and at the base of spines provide membrane and AMPARs to the synapse when using a protocol for learning known as long term potentiation (LTP). Although it is established that activity- dependent recruitment of REs to dendritic spines is essential for the expression of LTP, the precise location of RE docking for the delivery of receptors and membrane in dendrites remains obscure. Here, we have identified regions of exocytosis in dendritic spines that are positioned adjacent to the postsynaptic density. Further, we describe a putative molecular sensor, the adaptor molecule Rabi 1-FIP2 which aids in the correct membrane positioning of REs for proper spine exocytosis. This proposal will aim to (1) identify the signaling pathways required for Rabi 1-FIP2 spine localization (2) determine if disruption of Rabi 1-FIP2 mediates spine exocytosis and (3) define the functional consequences of Rabi 1-FIP2 disruption on facilitating delivery of AMPA receptors to spine membranes for the expression of LTP. Experiments will use a combination of basic biochemical approaches and live cell imaging in hippocampal neurons to identify the critical signaling pathways and requirement of Rabi 1-FIP2 for spine exocytosis. Further, organotypic hippocampal slices in combination with electrophysiology will be used to test the function of Rabi 1-FIP2 on LTP. Since exocytosis from REs is crucial for the proper deliver of AMPARs to the postsynaptic membrane, we propose that this Rabi 1-FIP2 dependent cellular mechanism is a key element for learning-related synaptic plasticity in the mammalian brain. Public information: The delivery of AMPA receptors (AMPARs) from intracellular compartments known as recycling endosomes to the postsynaptic membrane of synapses is a major cellular mechanism for learning- related synaptic plasticity in the brain. In addition, dysregulation of endosomal function and AMPAR trafficking in dendritic spines contributes to various neurological disorders such as Alzheimer's disease, Down's syndrome, and schizophrenia. This proposal will focus on identifying the molecular machinery that is critical for learning-related synaptic plasticity in the mammalian brain and will provide insight into how disruption of endosomal function leads to neurological disease.
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