Altered plasticity and hunting behavior in Shank3 mutant mice
Creators: name: Groves Kuhnle, Chelsea Elizabeth
Publisher: name: Brandeis University
Year: 2021
Subjects: Shank3
Plasticity

description: Autism associated disorders (AADs) affect tens of millions of people worldwide and encompass Autism Spectrum Disorder (ASD) and conditions such as Rett, Fragile X and Phelan McDermid Syndromes. This class of conditions are developmental neurological disorders that share common symptoms such as OCD-like behavior, difficulty learning language, sensory hypersensitivity, and social divergence, though the severity of these symptoms varies widely both within ASD and between differing AADs. As AAD symptoms manifest during development, one overarching theme of Autism research focuses on understanding the ways in which genetic factors associated with AADs affect plasticity mechanisms associated with the maturation of neural circuits. It is hoped that by understanding the effect of mutations to AAD-associated genes on neural plasticity and the behavior of circuits, it will be possible to relate these neural underpinnings to the behavioral symptoms associated with Autism. In this thesis I present work contributing to such an understanding of the loss of Shank3, a gene associated with Phelan McDermid syndrome and linked to severe cases of ASD. This work demonstrates that Shank3 is necessary for normal cortical homeostatic plasticity and circuit maturation in the visual cortex, and presents a profile of Shank3 loss in learning and performing the complex ethological behavior of cricket hunting.In the first section of this work, I investigated the effects of Shank3 loss in the visual cortex. While it was known prior to our study that Shank3 loss blocks Hebbian long term potentiation in the hippocampus, it was not known whether Shank3 is also necessary for homeostatic plasticity in central circuits. We showed through these experiments that Shank3 is indeed required for normal homeostatic plasticity during circuit maturation in the visual cortex, demonstrating that its loss impairs synaptic scaling, intrinsic homeostatic plasticity, firing rate homeostasis, and ocular dominance plasticity. By simultaneously investigating how fundamental homeostatic mechanisms as well as how circuit properties such as ocular dominance plasticity respond to Shank3 loss, we contribute evidence that the stability of circuits in the visual system is affected by loss of Shank3 due to disabled homeostatic mechanisms. We additionally show that both synaptic scaling up and the overgrooming phenotype observed in Shank3 knockout (KO) mice can be therapeutically rescued, contributing evidence that Shank3 abolishes homeostatic mechanisms via the GSK3 pathway.
description: Next, I investigated the effect of Shank3 loss on cricket hunting. While AADs are associated with a wide range of symptoms including learning difficulties and increased time in planning goal-directed actions expected to affect complex ethological tasks, it is only recently that hunting has been established as a paradigm for investigating such behaviors in mice. By investigating the behavior of both wild type and Shank3 KO mice during five days of cricket hunting, we find that both naive and experienced Shank3 KO mice hunt crickets less efficiently than their wild type littermates. Through detailed investigations of the behavior of both strains, we find that such differences are not a result of locomotive motor deficits or neophobia. Rather, they are caused by the ability of wild type mice to more rapidly and dynamically respond to their prey. We also find evidence that experienced wild type mice perform distinctive actions during cricket attack which Shank3 KO mice did not acquire as a result of training.
description: Through a series of investigations examining the effect of Shank3 loss on homeostatic plasticity, the behavior of visual cortical circuits and tactics employed by mice during cricket hunting, the work presented in this thesis thus establishes a profile of Shank3 deficiency in mice. These findings are consistent with multiple hypothesized mechanisms by which Shank3 loss affects hunting behavior, including perturbation of the superior colliculus necessary for mediating several aspects of hunting performance and loss of plasticity in the basal ganglia necessary for acquisition of goal directed actions. It is hoped that future work will build on these results to show which factors are responsible for effects of Shank3 loss on complex ethological behavior, and that this will contribute to our broader understanding of neurodivergence.