Affiliations: [a] Neurology Division, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA | [b] Department of Neurology, Case Western Reserve University, Cleveland, OH, USA | [c] School of Medicine, Case Western Reserve University, Cleveland, OH, USA
Correspondence:
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Corresponding author: Dr. John Stahl, Department of Neurology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-5040, USA. Tel.: +1 216 844 3170; Fax: +1 216 231 3461; E-mail: [email protected]
Abstract: Downbeat nystagmus (DBN) is a common eye movement complication of cerebellar disease. Use of mice to study pathophysiology of vestibulocerebellar disease is increasing, but it is unclear if mice can be used to study DBN; it has not been reported in this species. We determined whether DBN occurs in the ataxic mutant tottering, which carries a mutation in the Cacna1a gene for P/Q calcium channels. Spontaneous DBN occurred only rarely, and its magnitude did not exhibit the relationship to head tilt seen in human patients. DBN during yaw rotation was more common and shares some properties with the tilt-independent, gaze-independent component of human DBN, but differs in its dependence on vision. Hyperactivity of otolith circuits responding to pitch tilts is hypothesized to contribute to the gaze-independent component of human DBN. Mutants exhibited hyperactivity of the tilt maculo-ocular reflex (tiltMOR) in pitch. The hyperactivity may serve as a surrogate for DBN in mouse studies. TiltMOR hyperactivity correlates with hyperdeviation of the eyes and upward deviation of the head during ambulation; these may be alternative surrogates. Muscimol inactivation of the cerebellar flocculus suggests a floccular role in the tiltMOR hyperactivity and provides insight into the rarity of frank DBN in ataxic mice.
