Homeostatic synaptic scaling is an important form of plasticity thought to be essential for maintaining stable function in developing neural circuits. Synaptic scaling """"""""scales"""""""" the strength of all of a neuron's excitatory synaptic strengths up or down in the correct direction to stabilize neuronal firing rates. These homeostatic adjustments in synaptic weights are accomplished in large part through changes in the synaptic accumulation of GluA2-containing AMPAR at synapses, and appear to operate on all excitatory synaptic inputs onto a given neuron in response to changes in the neuron's own firing. Despite great recent interest, the molecular and biophysical mechanisms that enable this homeostatic adjustment of AMPAR abundance during synaptic scaling are still poorly understood, and many of the assumptions underlying this model of synaptic scaling (such as its global nature) remain largely untested. In this proposal we aim to illuminate the mechanisms that lead to enhanced synaptic AMPAR abundance during scaling up, and to test the idea that this form of plasticity acts on all excitatory inputs to stabilize neuronal firing in vivo. This proposal is built around or recent observation that the AMPAR-binding protein GRIP1 is essential for the regulated increase in synaptic AMPAR abundance during scaling up, and that this process requires direct interactions between GRIP1 and GluA2. Here we proposed to determine how (at the biophysical level) this regulated interaction between GluA2-GRIP1 drives an increase in synaptic AMPAR abundance, by using a variety of cutting edge imaging approaches. We will test two alternative models: first, that GRIP1 traffics to synapses along with AMPAR and enhances synaptic capture of the receptor, and second, that GRIP1 enhances synaptic delivery of modified AMPAR that have an enhanced affinity for synaptic scaffolds. Further, we will use the tools we have generated through these in vitro studies to selectively disrupt AMPAR trafficking during synaptic scaling up in vivo, in order to probe the mechanism and function of synaptic scaling within intact neocortical circuits.
The ability of neurons and circuits to maintain stable function is absolutely fundamental for maintaining brain health, and it is likely that the breakdown of homeostatic mechanisms contributes to a wide range of neurological disorders, including epilepsy, autism, and neurodegenerative diseases. By putting functional/molecular identities onto the constituents of the machinery that generates activity set-points, and illuminating how these operate within intact networks, these experiments will may generate a new set of strategies for tackling neurological disorders.
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