A major challenge in neuroscience is to understand how neuronal networks are modified through experience and how proteins/genes contribute to circuit modification. Neural circuits are refined during development through activity-dependent gene and protein expression. Similar macromolecular synthesis is essential for long-term forms of synaptic plasticity such as long-term potentiation (LTP) and depression (LTD). Efforts to identify molecules that underlie these forms of plasticity have revealed a set of genes that target to excitatory synapses. Among these, Arc is the most tightly coupled to behavioral encoding of information in neuronal circuits. Arc homeostatically regulates surface AMPA type glutamate receptors (AMPARs) by directly interacting with the endocytic machinery. However, very little is known about Arc's function at the level of neuronal circuits or its precise in vivo role in mediating information storage. The visual cortex is an ideal preparation to probe these questions as visual experience can be modulated to induce gross changes in neuronal activity. The overall goal of this proposal is to investigate the mechanisms that underlie Arc's role in modifying neural circuits in response to visual experience and how these processes are disrupted in neurological disorders. In previous experiments, we find that Arc plays a fundamental role in experience- dependent plasticity in mouse visual cortex (V1). Arc knocks out mice exhibit deficits in ocular dominance plasticity and in a newly discovered form of experience-dependent plasticity, stimulus-specific response potentiation. We also uncover an experience and Arc-dependent component to establishing the contralateral to ipsilateral ratio. How does Arc regulate experience-dependent plasticity in the visual cortex? The goal of aim 1 is to investigate the mechanisms underlying these phenotypes by utilizing slice electrophysiology in V1 cortical slices and investigating the role of Arc in 3 different types of synaptic plasticity;LTD, LTP and synaptic scaling. In vivo electrophysiology provides a powerful tool to assess experience-dependent plasticity, but it is difficult to identify specific networks of individual cells. The goal of aim 2 is to investigate the role of Arc in experience- dependent plasticity at the single cell level using 2-photon calcium imaging in vivo, which can measure neuronal activity in many cells with spatial precision.
Aim 3 will directly test whether Arc mediates plasticity through its role in AMPAR trafficking. Finally, aim 4 intends to test the idea that Arc levels are critical for normal synaptic homeostasis and that abnormal Arc levels contribute to the synaptic dysfunction observed in neurological disorders, including Alzheimer's disease, Fragile X and Angelman Syndromes.
The overall goal of this proposal is to understand, at the molecular and cellular level, how experience shapes and modifies the brain. We will investigate the role of the activity-dependent gene Arc in synaptic and experience-dependent information storage in mouse visual cortex. We will also test the hypothesis that normal Arc levels are critical for brain function and that abnormal regulation of Arc expression contributes to the synaptic dysfunction observed in neurological disorders.
|Gee, J Michael; Smith, Nathan A; Fernandez, Fernando R et al. (2014) Imaging activity in neurons and glia with a Polr2a-based and cre-dependent GCaMP5G-IRES-tdTomato reporter mouse. Neuron 83:1058-72|