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The Role of Arc in Regulating Spine Morphology and Neural Network Stability In Vivo

  • Author(s): Peebles, Carol L.
  • Advisor(s): Finkbeiner, Steven M;
  • Davis, Graeme
  • et al.

The understanding of human memory is one of the greatest challenges facing neuroscience today. The brain's extraordinary ability to integrate information and appropriately adapt in response to various stimuli is at the core of learning and memory. At a cellular and molecular level, learning and memory relies on a neuron's ability to facilitate activity-dependent changes in synaptic efficacy. In order to better understand the mechanism behind such changes, we investigate the function of Arc, an immediate-early gene essential for both long-term and homeostatic plasticity. We find that through AMPA receptor endocytosis, Arc expression modulates spine morphology to favor more plastic thin spines and filopodia. Thus, Arc expression simultaneously reduces synaptic efficacy through AMPA receptor endocytosis while increasing structural plasticity by favoring thin spines. Supporting this, we find that loss of Arc in vivo leads to a decrease in the proportion of thin spines as well as neural network hyperexcitability. Given Arc's role in spine morphology we also investigate possible actin-regulating Arc-binding partners. We find that Arc directly binds to Wave3, an actin-nucleating factor, in neurons. We further demonstrate that reduction of Wave3 expression leads a marked decrease in primary dendrite length. In mature neurons, reduction of Wave3 results in decreased spine density and increased filopodia. Finally, Arc expression partially rescued these reductions in primary dendrite length and spine density, supporting a functional role for the Arc-Wave3 interaction. Thus, our investigations of Arc and Wave3 have contributed to the understanding of synaptic plasticity, and suggest new links between synaptic efficacy, structural plasticity, homeostasis and memory.

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