Date of Award

5-11-2009

Document Type

Thesis

Degree Name

Bachelor of Arts

First Advisor

McFarlane, Hewlet G.

Abstract

Autism is a severe neurodevelopmental disorder with comorbid behavioral deficits and of unknown etiology. Previous human studies have implicated abnormalities in the function and levels of two monoamines, dopamine (DA) and serotonin (5-HT), in the autistic brain. Using the BTBR T+tf/J inbred mouse strain that has recently emerged as an animal model with good face validity to all three core symptoms of autism (McFarlane et al., 2008), the present study investigated the regional brain monoamine levels and activity in BTBR in order to elucidate possible neurochemical substrates for the reported BTBR phenotypes and strengthen the model's applicability to the human disorder. The total DA tissue levels and the 5-HT turnover rate, measured as the tissue levels ratio of 5-HT's principal brain metabolite, 5-hydroxyindolacetic acid (5-HIAA), to 5-HT, were determined postmortem using high-performance liquid chromatography (HPLC) with electrochemical detection and compared between male juvenile (21 +/- 3 day-old) BTBR and C57BL/6J (B6) control mice for five brain regions of interest: the prefrontal cortex (PFC), the dorsal striatum or caudate putamen (CPu), the hippocampus (HP), the amygdala (AM) and the cerebellar cortex (CBC). The present findings indicated substantially lower DA tissue pools in the CPu and a strong trend suggestive of lower tissue DA availability in the PFC of BTBR compared to B6. A decrease in 5-HT turnover was observed in the AM and closely approached significance in the PFC, CPu, and HP of BTBR, implying lower regional 5-HT activity. The regional trends of 5-HT turnover decrease were supported by generally lower tissue levels of 5-HIAA, an indication of diminished 5-HT use, in the above BTBR regions. Overall, these results argue for lower regional baseline DA levels and 5-HT activity as substrates of the abnormal BTBR phenotypes relevant to autism.

Comments

Includes bibliographical references: pages 53-73

Rights Statement

All rights reserved. This copy is provided to the Kenyon Community solely for individual academic use. For any other use, please contact the copyright holder for permission.

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