Development of Oculomotor Circuits in Nystagmus

Infantile nystagmus syndrome is an involuntary oscillatory movement of the eyes that begins in infancy and persists throughout life. It is visually and socially debilitating. The underlying pathophysiology is poorly understood, and no effective treatments exist. More than half of infantile nystagmus patients have an associated retinal or optic nerve disorder. Nystagmus is thus thought to develop secondary to poor vision, suggesting that proper development of the oculomotor system is dependent on visual input, particularly in the first two months of life. The long-term goal of this research is to understand the pathophysiologic mechanisms in nystagmus and identify potential new therapeutic targets. Extraocular muscles (EOMs) from patients with infantile nystagmus display a number of abnormalities, including decreased innervation, small neuromuscular junctions, and an increased proportion of slow myofibers. We have recently shown that these changes are also present in a mouse model of nystagmus—albino mice—and that the first changes are present as early as P10, before eye opening. The human samples also show central nucleation of muscle fibers and an increase in expression of the immature form of acetylcholine receptor on the fast myofibers. These changes suggest that there is continuous remodeling of the EOM innervation in nystagmus. Different EOM myofiber types are innervated by different subtypes of oculomotor neurons (OMNs), which in turn receive different premotor inputs. The “fast” and “slow” OMNs, which innervate fast and slow myofibers, respectively, have different roles in different types of eye movements. EOMs, OMNs, and premotor inputs are all dependent on each other for survival. This leads to the hypothesis that nystagmus results from improper development of the oculomotor circuitry. This proposal aims to test this hypothesis in a mouse model of infantile nystagmus syndrome by (1) determining whether OMN survival and subtype distribution are altered and how the developmental timing of any changes relate to changes in EOM innervation and nystagmus onset and (2) determining whether the premotor synaptic inputs to the OMNs develop abnormally in mice with nystagmus. Albino mice, which display spontaneous nystagmus, will be assessed for changes in EOM innervation and myofiber subtypes and corresponding differences in OMN survival and subtype distribution. Age of onset of nystagmus will be determined. Viral transsynaptic tracing will delineate the first-order synaptic connections onto the ocular motor nuclei. In all experiments, albino mice will be compared to wild-type littermates, obtained from heterozygous matings, to control for genetic background. Multiple developmental timepoints will be assessed to determine the point in development when changes associated with nystagmus occur; whether changes in the EOMs, OMNs, or premotor inputs occur first; and which changes precede nystagmus onset. This research will provide fundamental knowledge into the mechanisms of infantile nystagmus. Understanding where and when the abnormalities in infantile nystagmus first arise is the first step in identifying potential therapeutic targets or preventative interventions.