Deficient experience-dependent plasticity in the visual cortex of Arc null mice

Abstract

Within the visual cortex a vast assortment of molecules work in concert to sharpen and refine neuronal circuits throughout development. With the advent of genetic mouse models it is now possible to probe the individual contributions of single molecules implicated in this process. The Arc (activity-regulated cytoskeletal associated) gene is an effector immediate early gene that has been suggested to play a critical role in synaptic plasticity. The goal of this thesis is to understand the workings of Arc within the visual cortex. Specifically, we ask how genetic deletion of Arc influences plasticity, and how visual response properties differ between cells types containing, and not containing Arc. To elucidate a role for Arc in visual cortical plasticity we took advantage of knockin mice expressing GFP in place of Arc protein (referred to as KO mice for simplicity). We combined intrinsic signal imaging, visually evoked potentials, and two-photon in vivo calcium imaging to assess plasticity in juvenile and adult wild-type (WT), heterozygote, and KO mice. We find that plasticity is disrupted in the visual cortex of Arc KO mice in the absence of obvious deficits at the level of basal response properties. In addition, this work has revealed that: 1) Arc is necessary for the establishment of normal ocular dominance during development and critical for deprived eye depression in the visual cortex of juvenile animals 2) Loss of Arc impairs AMPA receptor internalization in visual cortex- a necessary requirement for synaptic weakening after lid suture.

(cont.) 3) Open eye potentiation fails to occur after extended deprivation in the absence of Arc 4) Arc is required for stimulus response potentiation in juvenile animals. 5) Arc is not required for the synaptic scaling up of response suggesting a specific role in Hebbian plasticity. 6) Single cell analysis within the binocular zone of Arc-GFP homozygotes reveals that the distribution of Arc lacking GFP-positive cells does not display a contralateral-bias as compared to controls, and the majority of Arc-lacking GFP-positive cells receive equal input from each eye, suggesting that Arc is critical for synaptic weakening during development. Together, these experiments illustrate the essential role for Arc in experience-dependent plasticity within the visual system.