Disrupted Motor Neuron and Neuromuscular Junction Development in an Albino Mice Model of Infantile Nystagmus.

PURPOSE: Infantile nystagmus syndrome (INS) involves involuntary oscillatory eye movements, usually in the horizontal plane, beginning before six months of age. It is frequently associated with other eye diseases, including albinism. Pathological changes in the extraocular muscles (EOMs), including altered myofiber composition and decreased neuromuscular junction (NMJ) density, have been shown in albino mice and humans. METHODS: We examined motor neuron (MN) innervation and NMJ formation in EOMs of albino mice from early postnatal stages to adulthood using whole-mount immunostaining, immunohistochemistry and confocal microscopy. RESULTS: We found significant deficits in MN axon innervation, specifically in horizontal EOMs, beginning in the first postnatal week. Abnormal NMJ development was evident through decreased presynaptic axon contacts, reduced synaptophysin expression, delayed and abnormal maturation of acetylcholine receptor clusters, and fewer subsynaptic nuclei. Analysis of MN subpopulations in the oculomotor nucleus revealed an increased proportion of multiply-innervated muscle fiber (MIF)-innervating MNs, aligning with previous findings of increased MIF myofibers in EOMs. This difference in motor neuron subtypes occurred earlier (P10) than the differences in myofibers (P14), suggesting that type of MN innervation influences myofiber characteristics. Given their distinct electrophysiological properties and upstream inputs compared to singly-innervated muscle fiber (SIF)-innervating MNs, these results suggest early abnormalities in brainstem oculomotor circuits in albinos. CONCLUSIONS: The MN innervation and NMJ formation anomalies indicate a failure in establishing stable connections and mature synapses. These disruptions occur before eye opening, therefore are not secondary to low vision, and likely interfere with proper EOM function, contributing to INS pathogenesis.