The Role of Homer Scaffolding to Metabotropic Glutamate Receptor 5 in the Mouse Models of Neurodevelopement Disorders
| dc.contributor.advisor | Kavalali, Ege T. | en |
| dc.contributor.committeeMember | Albanesi, Joseph P. | en |
| dc.contributor.committeeMember | Parada, Luis F. | en |
| dc.contributor.committeeMember | Huber, Kimberly M. | en |
| dc.creator | Collins, Katie Anne | en |
| dc.date.accessioned | 2016-06-27T20:03:12Z | |
| dc.date.available | 2016-06-27T20:03:12Z | |
| dc.date.created | 2014-05 | |
| dc.date.issued | 2014-04-16 | |
| dc.date.submitted | May 2014 | |
| dc.date.updated | 2016-06-27T19:48:14Z | |
| dc.description.abstract | Autism is a neurological disorder characterized by repetetive behaviors, social anxiety and verbal and non-verbal communication. Fragile X Syndrome (FXS) is the most common genetic cause of autism and inheritable form of intellectual disability. FXS is caused by the transcriptional silencing of the Fmr1 gene, which encodes for the Fragile X Mental Retardation Protein (FMRP), which is a Ribonucleic acid (RNA) binding protein. FMRP binds to messenger RNA (mRNA) and suppresses their translation. FMRP regulates hundreds of mRNAs, making it a complex disease with several possible dysfunctions causing the many symptoms, like audiogenic seizures or hypersensitivity. While there are several studies which rescue phenotypes, there is little known about what causes the abnormalities, and if it is possible to replicate the symptoms with a single genetic manipulation. There is also little know about common links between different genetic causes of autism. In this study, I manipulate the interaction between metabotropic glutamate receptor 5 (mGluR5) and Homer, and report how these interactions are important in causing some of the phenotypes in FXS. By rescuing disrupted mGluR5-Homer interactions with a Homer 1a knock out I can rescue several phenotypes, and by disrupting mGluR5-Homer interactions with an mGluR5 knock-in mouse that is mutated so it cannot bind to Homer, I was able to mimic them. I was able to rescue/mimic increased basal translation, altered mGluR-signaling, increased neocortical excitability, decreased anxiety, and partial rescue/mimic audiogenic seizures seen in Fragile X mice. However, I was unable to rescue/mimic the enhanced mGluR-LTD. In this study, I also report how the disrupted mGluR5-Homer interactions are caused by Homer being phosphorylation by CaMKIIα. CaMKIIα is an FMRP target and elevated in the Fmr1 KO mice, causing increased phosphorylation of Homer. Inhibiting CaMKIIα, rescues mGluR5-Homer interactions, basal protein synthesis rates and increased neocortical excitability. Lastly, I report how in PTEN conditional KO (cKO) mice, another autism model, also have disrupted mGluR5-Homer interactions. The PTEN cKO mice have increased neocortical excitability, which can be rescued by inhibiting mGluR5. This suggests a common mGluR5 dysfunction in multiple autism models, which could lead to a common treatment. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 952355687 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/3308 | |
| dc.language.iso | en_US | en |
| dc.subject | Carrier Proteins | en |
| dc.subject | Fragile X Syndrome | en |
| dc.subject | Gene Expression Regulation | en |
| dc.subject | Receptors, Metabotropic Glutamate | en |
| dc.title | The Role of Homer Scaffolding to Metabotropic Glutamate Receptor 5 in the Mouse Models of Neurodevelopement Disorders | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Neuroscience | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |