The most well-established mechanism for the expression of the activity-dependent forms of synaptic plasticity known as long-term potentiation (LTP) and long-term depression (LTD) is the trafficking of AMPA receptors (AMPARs) into or out of the postsynaptic membrane. This trafficking is believed to be shaped in important ways by the identity of the particular receptor subunits present in the dendritic spine. The dominant model of AMPAR trafficking has held that the unique C-terminal tails of these subunits play an important role in sorting these receptors to their intended destination, whether it be in the surface membrane, specifically in the postsynaptic membrane, or at an intracellular site. Recently that model has been partly challenged by findings that suggest that AMPARs are not sorted by subunit composition, but rather that the primary driver of LTP induction is a change in the properties of the postsynaptic density and/or in dendritic spine volume that captures additional AMPARs in a subunit indiscriminate manner. Yet at the same time, previous data, including our own, strongly support the idea that specific AMPAR subunits in the postsynaptic membrane are crucial for the induction of LTP and the specification of defined synaptic plasticity states. This grant seeks to leverage the existing knowledge about the trafficking of AMPA receptors in a new series of experiments that combines our established techniques of paired-neuron electrophysiological recordings with our more recently acquired ability to use array tomography to track the location of glutamate receptor subunits on dendritic spines of synapses specifically known to have undergone plasticity. We will test competing hypotheses concerning the nature of AMPA receptor trafficking into postsynaptic membranes during the induction of synaptic plasticity.
This application is designed to study the mechanisms of brain function at the most fundamental level; how the brain learns and adapts to the environment via use-dependent changes in brain synapses. We will combine the powerful electrophysiological techniques with state-of-the-art tomographic anatomical techniques to study the mechanisms of change that synapses undergo when they are storing information. These processes are fundamental to everything the brain does, so understanding them will advance the understanding of brain function and pathology across a wide front.
|Valenzuela, Ricardo A; Micheva, Kristina D; Kiraly, Marianna et al. (2016) Array tomography of physiologically-characterized CNS synapses. J Neurosci Methods 268:43-52|