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Thesis Seminars


Age-related Neuropathological and Neurophysiological Changes of Auditory Processing in a Knockout Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

Yanya Ding - PhD Candidate, Advisors: Edward Freedman, PhD, John Foxe, PhD, and Kuan Hong Wang, PhD

CLN3 disease is one of the most prevalent forms of Neuronal Ceroid Lipofuscinosis (NCL), resulting from homozygous mutations in the human CLN3 gene. It is characterized by abnormal accumulation of ceroid lipofuscin in the lysosomes of multiple cell types, with neurons most severely affected. Individuals with CLN3 disease have early onset of blindness, motor deficits, and progressive declines in cognitive functioning and verbal intellectual abilities starting from juvenile age. However, effects of CLN3 mutations on auditory processing remain unknown. Although concurrent CLN3 mouse models successfully recapitulate ceroid lipofuscin accumulation and visual and motor deficits in humans, less is known about the link between cellular pathology and progression of disease phenotypes. Objective cross-species neurologic markers are also not well established. To fill these knowledge gaps, we will examine the effects of CLN3 mutations on auditory processing in terms of both ceroid lipofuscin accumulation and neurophysiological changes.

We hypothesize that CLN3 mutations induce cell type specific accumulation of ceroid lipofuscin and predispose neurons for neurophysiological changes and auditory processing deficits. In aim 1, we will determine whether ceroid lipofuscin preferentially accumulates in specific cell types in the CLN3 -/- mouse model. We will utilize confocal microscopy imaging of Subunit C of mitochondrial ATP Synthase (SCMAS), a common immunofluorescence marker for ceroid lipofuscin, to access accumulation of ceroid lipofuscin in different auditory processing brain regions across multiple time points. We will also test co-localization of SCMAS with parvalbumin (PV) to determine whether ceroid lipofuscin preferentially accumulates in PV + interneurons. Aim 2 will examine whether ceroid lipofuscin accumulation is associated with auditory electroencephalography (EEG) changes in the CLN3 -/- mouse model. We will conduct auditory duration mismatch negativity (MMN) to measure age-related neurophysiological changes. In aim 3, we will test whether CLN3 mutations disrupt the balance of excitatory and inhibitory neural activities in auditory processing. Fiber photometry Ca2+ imaging will be used to measure neural activity changes in PV-Cre CLN3 animals after viral injection of GCaMP6 reporter.

Overall, this project will provide a foundation to uncover longitudinal neuropathology of auditory processing in CLN3 disease and bridge the gap between current pathological and neurophysiological measurements. It will also help to develop auditory MMN as a clinically relevant biomarker and establish cross-species endophenotype.

 Nov 30, 2022 @ 1:00 p.m.
 Medical Center | Ryan Case Method Room (1-9576)