Abstract
Background
Niemann-Pick disease type C (NPC) is a lysosomal lipid-trafficking disorder with progressive neurodegeneration and cerebellar dysfunction. Although balance impairment is prominent, vestibular-system involvement remains poorly characterized.Objective
To determine whether altered vestibular-related reflex responses are detectable at P35 and how they relate to vestibular hair-cell morphology, cholesterol-associated changes, and cerebellar pathology in Npc1-/- mice.Methods
Female postnatal day 35 Npc1-/- and wild-type mice were studied using separate functional and histological cohorts (n = 5/genotype in each cohort). The functional cohort underwent vestibulo-ocular reflex (VOR), ocular counter-roll (OCR), caloric, locomotor, postural, and gait assessments. Myo7a immunofluorescence was used to evaluate the crista ampullaris, utricle, and saccule in the histological cohort. Filipin staining assessed unesterified cholesterol in the saccule. Cerebellar pathology was quantified as molecular-layer area relative to the analyzed cerebellar cortical area.Results
Npc1-/- mice showed significantly reduced OCR amplitudes and caloric responses, whereas VOR gain did not differ significantly between genotypes. Mutant mice had reduced spontaneous locomotor activity, shorter stride length, and a wider base of support; cadence and average walking speed did not differ significantly between genotypes. Vestibular hair-cell density remained preserved in all three sensory organs, whereas filipin labeling was increased in the saccule. The relative cerebellar molecular-layer area was significantly reduced.Conclusions
Npc1 deficiency is associated with altered vestibular-related reflex responses that coexist with preserved vestibular hair-cell morphology, cholesterol-associated changes in the saccule, and cerebellar pathology. These findings demonstrate vestibular-related physiological abnormalities but do not permit complete separation of peripheral and central contributions to the balance phenotype. Objective vestibular testing may provide complementary measures for characterizing disease-related balance dysfunction.