The Role of SHANK3 at the Synapse and Its Implications in Autism-Associated Behaviors and Synaptic Transmission

dc.contributor.advisorRothenfluh, Adrianen
dc.contributor.committeeMemberHuber, Kimberly M.en
dc.contributor.committeeMemberBibb, James A.en
dc.contributor.committeeMemberPowell, Craig M.en
dc.creatorKouser, Mehreenen
dc.date.accessioned2017-06-02T15:24:47Z
dc.date.available2017-06-02T15:24:47Z
dc.date.created2015-05
dc.date.issued2015-04-10
dc.date.submittedMay 2015
dc.date.updated2017-06-02T15:13:05Z
dc.descriptionPage xiv of the dissertation is incorrectly numbered as page xiii.en
dc.description.abstractAutism is a neurodevelopmental disorder characterized by an increase in repetitive behaviors and impairments in social interaction and communication. Since its discovery, a multitude of studies have linked SHANK3 to autism. Moreover, deletion of SHANK3 has been shown to cause Phelan McDermid Syndrome (22q13 Deletion Syndrome) by several human studies. Shank3 is a multi domain post-synaptic scaffolding proteins that is found in excitatory synapses and plays a critical role in forming the post-synaptic density by connecting the necessary machinery together. In this study, I have characterized a homozygous Shank3 mutation in mice that deletes exon 21(Shank3ΔC) including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major, naturally occurring Shank3 protein bands. Shank3ΔC/ΔC mice exhibit an increased localization of mGluR5 to the synapses in the hippocampus, a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. I also report on a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3G) which causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse like the Shank3ΔC/ΔC mice. Shank3G/G mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, and altered response to novelty. Shank3G/G mice also exhibit impaired hippocampal excitatory transmission and plasticity. Finally, Shank3G/G mice were designed to be genetically rescued to wild-type at various times during development. In this study, I also report on the biochemical and behavioral results of the genetic rescue in Shank3G/G mice after the completion of neurodevelopment. I was able to achieve a biochemical rescue in the Shank3G/G mice. Interestingly, not all the behavioral impairments observed in Shank3G/G mice were replicated in the Reversible-Shank3G/G mutation mice making the interpretation of the data more challenging which is discussed in detail in this thesis.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc988778279
dc.identifier.urihttps://hdl.handle.net/2152.5/4107
dc.language.isoenen
dc.subjectExonsen
dc.subjectMental Disordersen
dc.subjectMutagenesis, Insertionalen
dc.subjectMutationen
dc.subjectNerve Tissue Proteinsen
dc.subjectSynaptic Transmissionen
dc.titleThe Role of SHANK3 at the Synapse and Its Implications in Autism-Associated Behaviors and Synaptic Transmissionen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineNeuroscienceen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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