The use of an antisense oligonucleotide (ASO) therapy to restore vestibular function in the mouse model of usher syndrome
Wallace, Douglas G.
M.A. (Master of Arts)
Department of Psychology
Neurosciences; Cognitive psychology
Usher syndrome is an autosomal recessive disorder that results in impaired visual, auditory and vestibular function. In mouse models, Usher syndrome manifests itself through abnormal behaviors such as circling, poor auditory brainstem responses, and a decline in harmonin expression. Animals utilize several sources of information to guide spatial navigation (e.g., visual cues, vestibular input). Usher syndrome disrupts these essential sensory modalities. Recent work has demonstrated that an antisense oligonucleotide (ASO) therapy can attenuate the auditory deficit of Usher syndrome through an increase in harmonin production and correct splicing. However, it has yet to be determined if this therapy can also rescue vestibular function and the impaired spatial orientation that is associated with vestibular pathologies. The current study examines the effect of Usher syndrome and an ASO therapy on the organization of exploratory movements under dark and light testing conditions. Heterozygous and mutant Usher mice received an infusion of ASO or a control infusion at postnatal day five. At two-months of age, mouse exploratory behavior was recorded for 50 minutes during three consecutive dark sessions followed by three consecutive light sessions. Motion capture software was used to segment the movement paths into progressions and stops, which was utilized to determine exploratory movement organization. Mutant Usher mice demonstrated irregular exploratory movements compared to heterozygous mice. The ASO therapy attenuated these disruptions in exploratory movement organization. These results demonstrate the potential for an ASO therapy to ameliorate spatial orientation deficits associated with Usher syndrome. Further research is needed to assess the effectiveness of ASO therapy at different time points following treatment and to characterize the effects of ASO therapy on neural systems that mediate exploratory movement organization.
Donaldson, Tia Nicole, "The use of an antisense oligonucleotide (ASO) therapy to restore vestibular function in the mouse model of usher syndrome" (2018). Graduate Research Theses & Dissertations. 6363.
Northern Illinois University
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Advisor: Wallace, Douglas.||Committee members: Grippo, Angela; Hastings, Michelle; Matuszewich, Leslie.||Includes bibliographical references.