Graduation Date

5-2016

Document Type

Master's Thesis

Degree Name

Master of Science

Department or Program

Biological Sciences

Department or Program Chair

Maggie Louie, PhD

First Reader

Manuel Lopez, PhD

Second Reader

Ekaterina Kalashnikova, PhD

Abstract

Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disease caused by a mutation in the gene that codes for the enzyme heparan sulfamidase. The decreased enzyme activity of heparan sulfamidase results in the accumulation of heparan sulfate (HS). HS accumulation in the brain causes severe central nervous system (CNS) complications, including learning and memory deficits and seizure. MPS IIIA patients have short life expectancies and there currently is no cure for the disease. This thesis work was aimed at identifying an early neurological phenotype in the mouse model of MPS IIIA. The data will aid in the design of an in vivo assay for CNS correction for drug discovery. The tests for learning and memory impairments using the Barnes maze and novel object recognition behavioral assays did not show a neurological defect earlier than 20 weeks. These results suggest an intact cognitive capacity for the diseased animals. To test whether seizure threshold is altered in diseased animals, mice were administered with the chemiconvulsant drug, pentylenetetrazol (PTZ), a GABA receptor inhibitor. The acute intravenous infusion with PTZ did not show threshold differences between the diseased and normal mice. However, chronic administration of a subconvulsive dose of PTZ, resulted in a difference in seizure sensitization or kindling, as early as 4 weeks. MPS IIIA mice showed significant resistance to kindling by 12 weeks. These seizure results not only demonstrate that we can record a CNS specific phenotype earlier than 20 weeks, it also suggests that neuroplasticity may be altered in diseased animals. Thus, this seizure assay may help understand the alterations that occur in the brain circuitry of MPS IIIA affected animals.

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