Neural Mechanisms and Behaviors in Models of Conditional Nprl2 Loss

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dc.contributor.advisorJohnson, Jane E.en
dc.contributor.committeeMemberTu, Benjaminen
dc.contributor.committeeMemberPascual, Juan M.en
dc.contributor.committeeMemberTsai, Peteren
dc.creatorDentel, Brianne Marieen
dc.creator.orcid0000-0003-4384-3529
dc.date.accessioned2022-09-20T17:17:29Z
dc.date.available2022-09-20T17:17:29Z
dc.date.created2020-08
dc.date.issued2020-08-01T05:00:00.000Z
dc.date.submittedAugust 2020
dc.date.updated2022-09-20T17:17:30Z
dc.descriptionThe file named "DENTEL-PRIMARY-2022-1.pdf" is the primary dissertation file. Two (2) supplemental video files are also available and may be viewed individually.en
dc.description.abstractThe amino acid sensitive arm of mTORC1 regulation signals through the GATOR1 complex. Loss of function of GATOR1 contributes to several neurodevelopmental disorders and medically refractive epilepsy. Mutations to one of the essential subunits of GATOR1, NPRL2, are sufficient to cause focal epilepsy and schizophrenia; yet, little is known about its role in the nervous system. Here we demonstrate the loss of Nprl2 in excitatory cells in the neocortex and hippocampus is sufficient to cause mTOR-related pathology, decreased survival and spontaneous seizures. By inhibiting mTOR activity with rapamycin we were able to rescue brain size, seizures and survival. We also show that loss of Nprl2 results in a down-regulation of synaptic proteins, and several metabolic disruptions. Furthermore, we demonstrated that the significantly increased glycine was a primary mechanism which increased synaptic excitability. This suggests that targeting the glycine binding site on the NMDA receptor may be a targeted therapy for future study. We also demonstrated, in three different cell-specific conditional knockout models, distinct behavioral profiles which points to the importance of Nprl2 in various neurodevelopmental disorders. These findings demonstrate the multifaceted effects of Nprl2 loss in excitatory cells- which demonstrate seizures and early mortality; excitatory and inhibitory neurons- which had seizures, hyperactivity, social and learning deficits; inhibitory cells- which demonstrated severe hyperactivity, social and learning deficits; and Purkinje cell-specific loss- which had seizure susceptibility, reversal learning deficits and delayed-onset social deficits and altered PPI. These findings highlight the significant role NPRL2 has in the nervous system and future studies in these models will aid in understanding and potentially developing targeted therapies to address the molecular and cellular mechanisms underlying NDDs and seizures in NPRL2 loss.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1345260474
dc.identifier.urihttps://hdl.handle.net/2152.5/9975
dc.language.isoenen
dc.subjectEpilepsies, Partialen
dc.subjectEpilepsyen
dc.subjectGenetic Predisposition to Diseaseen
dc.subjectMechanistic Target of Rapamycin Complex 1en
dc.subjectNeurodevelopmental Disordersen
dc.subjectTumor Suppressor Proteinsen
dc.titleNeural Mechanisms and Behaviors in Models of Conditional Nprl2 Lossen
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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