Oculomotor Instabilities in Zebrafish Mutantbelladonna: A Behavioral Model for Congenital Nystagmus Caused by Axonal Misrouting

Abstract

A large fraction of homozygous zebrafish mutant belladonna (bel) larvae display a reversed optokinetic response (OKR) that correlates with failure of the retinal ganglion cells to cross the midline and form the optic chiasm. Some of these achiasmatic mutants display strong spontaneous eye oscillations (SOs) in the absence of motion in the surround. The presentation of a stationary grating was necessary and sufficient to evoke SO. Both OKR reversal and SO depend on vision and are contrast sensitive.We built a quantitative model derived from bel fwd (forward) eye behaviors. To mimic the achiasmatic condition, we reversed the sign of the retinal slip velocity in the model, thereby successfully reproducing both reversed OKR and SO. On the basis of the OKR data, and with the support of the quantitative model, we hypothesize that the reversed OKR and the SO can be completely attributed to RGC misrouting. The strong resemblance between the SO and congenital nystagmus (CN) seen in humans with defective retinotectal projections implies that CN, of so far unknown etiology, may be directly caused by a projection defect.

Zebrafish: A model system for the study of eye genetics

“…Cloning of the mutant loci identified a point mutation in the gene encoding the lim domain transcription factor Lhx2 (Seth, et al, 2006); neither gene function nor expression data provide an immediate clue to the molecular mechanism leading to the behavioral mutant phenotype. Rather, based upon careful scrutiny of the behavioral deficit (Huang, et al, 2006;Rick, et al, 2000) it was proposed that: in the wild-type fish, visual stimulation of one eye drives movement of that eye through projections to a contralateral OKRmediated nucleus and integrator nucleus that ultimately controls the ipsilateral motor nuclei and the ocular muscles of the stimulated eye ( Figure 5; (Rick et al, 2000)). In this model, the neural basis of the altered behavior in bel mutants can be attributed to the singular defect in the projection of ganglion cell axons to the ipsilateral OKR-mediated nucleus.…”

Analysis of Optokinetic Response in Zebrafish by Computer-Based Eye Tracking

“…In our laboratory, different processing methods have been applied in the past depending on the research question ( 11,13,16,17 ) . Here, we describe in detail the method of choice for a rapid screening of vision defects.…”

“…For this kind of quantitative analysis, we refer to our work on the mutant belladonna ( 16 ) . A fraction of the homozygous belladonna larvae displays a reversed OKR and spontaneous eye oscillations in the absence of a moving stimulus.…”

“…We then describe our standard eye movement quanti fi cation approach which allows for detection of subjects with vision defects as well as for investigation of the OKR behavior itself. Since our system is under continuous development ( 1,2,11,13,16,17 ) , some of the details described in the protocol may change over time. However, our detailed protocol should enable the reader to apply the methodology of quantitative OKR measurements.…”

Application of zebrafish oculomotor behavior to model human disorders

“…The zebrafi sh OKR has been successfully used to characterize visual performance Nicola , 1996, 1997 ;Haug et al , 2010 ) to pinpoint defects in visual performance or visual pathway abnormalities (Rick et al , 2000 ;Huang et al , 2006 ) and to study how the retina decodes motion (Orger et al , 2000 ;Roeser and Baier , 2003 ). Nicola (1996, 1997) undertook a detailed analysis of the development of the larval zebrafi sh oculomotor system.…”