Date of Award

5-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Neuroscience

Research Advisor

Detlef H. Heck, Ph.D.

Committee

John D. Boughter, Ph.D. Robert C. Foehring, Ph.D. Robert S. Waters, Ph.D. Fu-Ming Zhou, Ph.D.

Abstract

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. It is caused by a mutation in the fragile X mental retardation (FMR1) gene on the X chromosome. Many children with FXS exhibit autistic behaviors and deficits in motor coordination including speech articulation deficits. The development of the FMR1 knockout (Fmr1 KO) mouse, in which the Fmr1 gene is inactivated, has provided an animal model that can be used to investigate underlying neuro-physiological mechanisms associated with FXS as well as to evaluate potential therapeutic treatments. In this study, quantitative behavioral assays were used, such as long term fluid licking observations, measurements of ultrasonic vocalizations (USV), and 3D tracking of whisker movements to test Fmr1 KO mice for behavioral deficits compared to their Wild type (WT) littermates. Electrophysiological techniques were employed to evaluate the functional properties of the neocortex. Pyramidal neurons in the neocortex of human FXS patients and Fmr1 KO mice are characterized by abnormally long, thin and numerous dendritic spines. Multiple electrode recordings were used to study how loss of Fmr1 expression affects several aspects of the neocortical network activities in Fmr1 KO mice. Single and multi unit spike activities and local field potentials (LFPs) were recorded in the whisker barrel cortex of awake mice. Baseline spike activity was significantly lower in cortical neurons of Fmr1 KO mice. Synchronous activity at the LFP was strongly reduced in Fmr1 KO mice. Relative power in the delta range frequency band of LFP activity was significantly reduced in the neocortex of Fmr1 KO mice. Furthermore, relative power in the beta frequency band was significantly higher in Fmr1 KO compared to WT mice. Our behavioral assays identified several phenotypical differences between Fmr1 KO and WT mice. Orofacial behavioral deficits in fluid licking and USV may be comparable to speech deficits in fragile X patients. Severely impaired dynamics of neocortical network activity may be causally linked to the cognitive and sensorimotor impairments associated with fragile X syndrome.

DOI

10.21007/etd.cghs.2012.0268

Comments

Two year embargo expired May 2014

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