Long-term exposure to bisphenol S damages the visual system and reduces the tracking capability of male zebrafish (Danio rerio).

Bisphenol S (BPS) is widely detected in aquatic environments and in human bodies. BPS has reproductive and thyroid disrupting effects, but its effect on the visual system remains unknown. In the present study, zebrafish embryos were exposed to BPS at concentrations of 1, 10, 100 and 1000 µg l-1 until 120 days post-fertilization in a semistatic system, and the effect of BPS on the visual behavior was examined using the optokinetic response and the optomotor response tests in male zebrafish. The retinal histology, mRNA expression of photoreceptor opsin genes (zfrho, zfblue, zfgr1, zfred and zfuv) and apoptosis-related genes (bax and bcl-2) were also assessed. Long-term BPS exposure decreased the tracking capability of male zebrafish, consistent with structural damage to the retina. BPS induced different amounts of vacuoles in the retinal pigment epithelium, and 1000 µg l-1 BPS exposure decreased the length of the inner plexiform layer, ganglion cell layer and retina, and induced an irregular arrangement of photoreceptor cells. The expression levels of the opsin genes (zfred, zfgr1 and zfrho) were significantly elevated, indicating an enhanced spectral sensitivity to red, green and dim light to compensate for the reduction of the optomotor response. Together, the results showed for the first time that long-term exposure to BPS damaged the structure of male zebrafish retina and reduced their tracking capability.

Adaptive Acceleration of Visually Evoked Smooth Eye Movements in Mice.

UNLABELLED: The optokinetic response (OKR) consists of smooth eye movements following global motion of the visual surround, which suppress image slip on the retina for visual acuity. The effective performance of the OKR is limited to rather slow and low-frequency visual stimuli, although it can be adaptably improved by cerebellum-dependent mechanisms. To better understand circuit mechanisms constraining OKR performance, we monitored how distinct kinematic features of the OKR change over the course of OKR adaptation, and found that eye acceleration at stimulus onset primarily limited OKR performance but could be dramatically potentiated by visual experience. Eye acceleration in the temporal-to-nasal direction depended more on the ipsilateral floccular complex of the cerebellum than did that in the nasal-to-temporal direction. Gaze-holding following the OKR was also modified in parallel with eye-acceleration potentiation. Optogenetic manipulation revealed that synchronous excitation and inhibition of floccular complex Purkinje cells could effectively accelerate eye movements in the nasotemporal and temporonasal directions, respectively. These results collectively delineate multiple motor pathways subserving distinct aspects of the OKR in mice and constrain hypotheses regarding cellular mechanisms of the cerebellum-dependent tuning of movement acceleration. SIGNIFICANCE STATEMENT: Although visually evoked smooth eye movements, known as the optokinetic response (OKR), have been studied in various species for decades, circuit mechanisms of oculomotor control and adaptation remain elusive. In the present study, we assessed kinematics of the mouse OKR through the course of adaptation training. Our analyses revealed that eye acceleration at visual-stimulus onset primarily limited working velocity and frequency range of the OKR, yet could be dramatically potentiated during OKR adaptation. Potentiation of eye acceleration exhibited different properties between the nasotemporal and temporonasal OKRs, indicating distinct visuomotor circuits underlying the two. Lesions and optogenetic manipulation of the cerebellum provide constraints on neural circuits mediating visually driven eye acceleration and its adaptation.

Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina.

Microglia, the principal resident immune cell of the CNS, exert significant influence on neurons during development and in pathological situations. However, if and how microglia contribute to normal neuronal function in the mature uninjured CNS is not well understood. We used the model of the adult mouse retina, a part of the CNS amenable to structural and functional analysis, to investigate the constitutive role of microglia by depleting microglia from the retina in a sustained manner using genetic methods. We discovered that microglia are not acutely required for the maintenance of adult retinal architecture, the survival of retinal neurons, or the laminar organization of their dendritic and axonal compartments. However, sustained microglial depletion results in the degeneration of photoreceptor synapses in the outer plexiform layer, leading to a progressive functional deterioration in retinal light responses. Our results demonstrate that microglia are constitutively required for the maintenance of synaptic structure in the adult retina and for synaptic transmission underlying normal visual function. Our findings on constitutive microglial function are relevant in understanding microglial contributions to pathology and in the consideration of therapeutic interventions that reduce or perturb constitutive microglial function. SIGNIFICANCE STATEMENT: Microglia, the principal resident immune cell population in the CNS, has been implicated in diseases in the brain and retina. However, how they contribute to the everyday function of the CNS is unclear. Using the model of the adult mouse retina, we examined the constitutive role of microglia by depleting microglia from the retina. We found that in the absence of microglia, retinal neurons did not undergo overt cell death or become structurally disorganized in their processes. However, connections between neurons called synapses begin to break down, leading to a decreased ability of the retina to transmit light responses. Our results indicate that retinal microglia contribute constitutively to the maintenance of synapses underlying healthy vision.

Effects of the jimpy mutation on mouse retinal structure and function.

The Jimpy mutant mouse has a point mutation in the proteolipid protein gene (plp1). The resulting misfolding of the protein leads to oligodendrocyte death, myelin destruction, and failure to produce adequately myelinated axons in the central nervous system (CNS). It is not known how the absence of normal myelination during development influences neural function. We characterized the Jimpy mouse retina to find out whether lack of myelination in the optic nerve during development has an effect on normal functioning and morphology of the retina. Optokinetic reflex measurements showed that Jimpy mice had, in general, a functional visual system. Both PLP1 antibody staining and reverse transcriptase-polymerase chain reaction for plp1 mRNA showed that plp1 is not expressed in the wild-type retina. However, in the optic nerve, plp1 is normally expressed, and consequently, in Jimpy mutant mice, myelination of axons in the optic nerve was mostly absent. Nevertheless, neither axon count nor axon ultrastructure in the optic nerve was affected. Physiological recordings of ganglion cell activity using microelectrode arrays revealed a decrease of stimulus-evoked activity at mesopic light levels. Morphological analysis of the retina did not show any significant differences in the gross morphology, such as thickness of retinal layers or cell number in the inner and outer nuclear layer. The cell bodies in the inner nuclear layer, however, were larger in the peripheral retina of Jimpy mutant mice. Antibody labeling against cell type-specific markers showed that the number of rod bipolar and horizontal cells was increased in Jimpy mice. In conclusion, whereas the Jimpy mutation has dramatic effects on the myelination of retinal ganglion cell axons, it has moderate effects on retinal morphology and function.

The effects of nicotine on cone and rod b-wave responses in larval zebrafish.

Acetylcholine is present in and released from starburst amacrine cells in the inner plexiform layer (IPL), but its role in retinal function except, perhaps, in early development, is unclear. Nicotinic acetylcholine receptors are thought to be present on ganglion, amacrine, and bipolar cell processes in the IPL, and it is known that acetylcholine increases the spontaneous and light-evoked responses of retinal ganglion cells. The effects of acetylcholine on bipolar cells are not known, and here we report the effects of nicotine on the b-wave of the electroretinogram in larval zebrafish. The b-wave originates mainly from ON-bipolar cells, and the larval zebrafish retina is cone-dominated. Only small rod responses can be elicited with dim lights in wild-type larval zebrafish retinas, but rod responses can be recorded over a range of intensities in a mutant ( n o optokinetic response f ) fi sh that has no cone function. We fi nd that nicotine strongly enhances cone-driven b-wave response amplitudes but depresses rod driven b-wave response amplitudes without, however, affecting rod- or cone-driven b-wave light sensitivity.

Contributions of retinal direction-selective ganglion cells to optokinetic responses in mice.

In the mouse retina, there are two distinct groups of direction-selective ganglion cells, ON and ON-OFF, that detect movement of visual images. To understand the roles of these cells in controlling eye movements, we studied the optokinetic responses (OKRs) of mutant mice with dysfunctional ON-bipolar cells that have a functional obstruction of transmission to ON direction-selective ganglion cells. Experiments were carried out to examine the initial and late phases of OKRs. The initial phase was examined by measurement of eye velocity using stimuli of sinusoidal grating patterns of various spatiotemporal frequencies that moved for 0.5 s. The mutant mice showed significant initial OKRs, although the range of spatiotemporal frequencies that elicited these OKRs was limited and the response magnitude was weaker than that in wild-type mice. To examine the late phase of the OKRs, the same visual patterns were moved for 30 s to induce alternating slow and quick eye movements (optokinetic nystagmus) and the slow-phase eye velocity was measured. Wild-type mice showed significant late OKRs with a stimulus in an appropriate range of spatiotemporal frequencies (0.0625-0.25 cycles/°, 0.75-3.0 Hz, 3-48°/s), but mutant mice did not show late OKRs in response to the same visual stimuli. The results suggest that two groups of direction-selective ganglion cells play different roles in OKRs: ON direction-selective ganglion cells contribute to both initial and late OKRs, whereas ON-OFF direction-selective ganglion cells contribute to OKRs only transiently.

Transgenic zebrafish expressing mutant human RETGC-1 exhibit aberrant cone and rod morphology.

Cone-rod dystrophy 6 (CORD6) is an inherited blindness that presents with defective cone photoreceptor function in childhood, followed by loss of rod function. CORD6 results from mutations in GUCY2D, the human gene encoding retinal guanylate cyclase 1 (RETGC-1). RETGC-1 functions in phototransduction, synthesising cGMP to open ion channels in photoreceptor outer segments. As there is limited histopathological data on the CORD6 retina, our goal was to generate a CORD6 model by expressing mutant human RETGC-1 in zebrafish cone photoreceptors and to investigate effects on retinal morphology and function. cDNAs encoding wildtype and mutant (E837D R838S) RETGC-1 were cloned under the control of the cone-specific gnat2 promoter and microinjected into zebrafish embryos to generate transgenic lines. RETGC-1 mRNA expression in zebrafish eyes was confirmed by RT-PCR. Fluorescent microscopy analysed retinal morphology and visual behaviour was quantified by the optokinetic response (OKR). Stable transgenic lines expressing mutant or wildtype human RETGC-1 in zebrafish eyes were generated. OKR assays of 5-day-old larvae did not uncover any deficits in visual behaviour. However, transgenic (E837D R838S) RETGC-1 expression results in aberrant cone morphology and a reduced cone density. A reduction in the number of photoreceptor nuclei, the thickness of the outer nuclear layer and the labelling of rod outer segments, particularly in the central retina, was evident. Expression of mutant human RETGC-1 leads to a retinal phenotype that includes aberrant photoreceptor morphology and a reduced number of photoreceptors. This phenotype likely explains the compromised visual function, characteristic of CORD6.

The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus.

Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.

Corticotropin-releasing factor critical for zebrafish camouflage behavior is regulated by light and sensitive to ethanol.

The zebrafish camouflage response is an innate "hard-wired" behavior that offers an excellent opportunity to explore neural circuit assembly and function. Moreover, the camouflage response is sensitive to ethanol, making it a tractable system for understanding how ethanol influences neural circuit development and function. Here we report the identification of corticotropin-releasing factor (CRF) as a critical component of the camouflage response pathway. We further show that ethanol, having no direct effect on the visual sensory system or the melanocytes, acts downstream of retinal ganglion cells and requires the CRF-proopiomelanocortin pathway to exert its effect on camouflage. Treatment with ethanol, as well as alteration of light exposure that changes sensory input into the camouflage circuit, robustly modifies CRF expression in subsets of neurons. Activity of both adenylyl cyclase 5 and extracellular signal-regulated kinase (ERK) is required for such ethanol-induced or light-induced plasticity of crf expression. These results reveal an essential role of a peptidergic pathway in camouflage that is regulated by light and influenced by ethanol at concentrations relevant to abuse and anxiolysis, in a cAMP-dependent and ERK-dependent manner. We conclude that this ethanol-modulated camouflage response represents a novel and relevant system for molecular genetic dissection of a neural circuit that is regulated by light and sensitive to ethanol.

[Neuro-ophthalmological and ophthalmological findings in Joubert syndrome]. / Neuroophthalmologische und ophthalmologische Befunde beim Joubert-Syndrom.

BACKGROUND: Joubert syndrome (JS) belongs to the ciliopathies and is a mostly autosomal recessively inherited disease (in the case of OFD1 mutations, JS is an X-linked trait). It is characterised by midbrain-hindbrain malformations with developmental delay, hypotonia and ataxia and a broad spectrum of other facultative findings. The aim of our study was to examine the ophthalmological and neuro-ophthalmological features of JS in our patients and to compare our findings to those of other studies. METHODS: In a retrospective study we evaluated the ophthalmological and neuro-ophthalmological findings of 9 consecutive patients who met the diagnostic criteria of JS. RESULTS: All patients had abnormalities of ocular motility, 4/9 used head thrusts to shift gaze (oculomotor apraxia OMA). In 6/8 patients, the optokinetic reflex (OKN) was absent. Furthermore, 8/9 children showed nystagmus, mostly see-saw nystagmus. Manifest strabismus was found in 8/9 while 3/9 had a retinopathy with either abnormal ERG and/or fundus appearance with or without visual impairment. Chorioretinal colobomata were present in 5/9 cases. Two patients showed a unilateral congenital ptosis, one a facial nerve paresis. CONCLUSIONS: The early neuro-ophthalmological findings in JS are not pathognonomic, but may lead to the diagnosis of JS. The syndrome should be suspected in patients with nystagmus, especially see-saw nystagmus, and abnormal OKN and/or OMA, and/or colobomata of the fundus, and further paediatric examinations should be initiated.

Distinct retinal deficits in a zebrafish pyruvate dehydrogenase-deficient mutant.

Mutations in ubiquitously expressed metabolic genes often lead to CNS-specific effects, presumably because of the high metabolic demands of neurons. However, mutations in omnipresent metabolic pathways can conceivably also result in cell type-specific effects because of cell-specific requirements for intermediate products. One such example is the zebrafish noir mutant, which we found to be mutated in the pdhb gene, coding for the E1 beta subunit of the pyruvate dehydrogenase complex. This vision mutant is described as blind and was isolated because of its vision defect-related darker appearance. A detailed morphological, behavioral, and physiological analysis of the phenotype revealed an unexpected specific effect on the retina. Surprisingly, the cholinergic amacrine cells of the inner retina are affected earlier than the photoreceptors. This might be attributable to the inability of these cells to maintain production of their neurotransmitter acetylcholine. This is reflected in an earlier loss of motion vision, followed only later by a general loss of light perception. Since both characteristics of the phenotype are attributable to a loss of acetyl-CoA production by pyruvate dehydrogenase, we used a ketogenic diet to bypass this metabolic block and could indeed partially rescue vision and prolong survival of the larvae. The noir mutant provides a case for a systemic disease with ocular manifestation with a surprising specific effect on the retina given the ubiquitous requirement for the mutated gene.

Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision.

Using the photopigment melanopsin, intrinsically photosensitive retinal ganglion cells (ipRGCs) respond directly to light to drive circadian clock resetting and pupillary constriction. We now report that ipRGCs are more abundant and diverse than previously appreciated, project more widely within the brain, and can support spatial visual perception. A Cre-based melanopsin reporter mouse line revealed at least five subtypes of ipRGCs with distinct morphological and physiological characteristics. Collectively, these cells project beyond the known brain targets of ipRGCs to heavily innervate the superior colliculus and dorsal lateral geniculate nucleus, retinotopically organized nuclei mediating object localization and discrimination. Mice lacking classical rod-cone photoreception, and thus entirely dependent on melanopsin for light detection, were able to discriminate grating stimuli from equiluminant gray and had measurable visual acuity. Thus, nonclassical retinal photoreception occurs within diverse cell types and influences circuits and functions encompassing luminance as well as spatial information.

Optogenetic localization and genetic perturbation of saccade-generating neurons in zebrafish.

The optokinetic response (OKR) to a visual stimulus moving at constant velocity consists of a series of two alternating components, a slow phase, during which the eyes follow the stimulus, and a quick phase, which resets the eyes to begin a new response cycle. The quick phases of the OKR resemble the saccades observed during free viewing. It is unclear to what extent the premotor circuitry underlying these two types of jerky, conjugate eye movements is conserved among vertebrates. Zebrafish (Danio rerio) larvae, broadly expressing halorhodopsin (NpHR) or channelrhodopsin-2 (ChR2) in most neurons, were used to map the location of neurons involved in this behavior. By blocking activity in localized groups of NpHR-expressing neurons with an optic fiber positioned above the head of the fish and by systematically varying the site of photostimulation, we discovered that activity in a small hindbrain area in rhombomere 5 was necessary for saccades to occur. Unilateral block of activity at this site affected behavior in a direction-specific manner. Inhibition of the right side suppressed rightward saccades of both eyes, while leaving leftward saccades unaffected, and vice versa. Photostimulation of this area in ChR2-transgenic fish was sufficient to trigger saccades that were precisely locked to the light pulses. These extra saccades could be induced both during free viewing and during the OKR, and were distinct in their kinetics from eye movements elicited by stimulating the abducens motor neurons. Zebrafish double indemnity (didy) mutants were identified in a chemical mutagenesis screen based on a defect in sustaining saccades during OKR. Positional cloning, molecular analysis, and electrophysiology revealed that the didy mutation disrupts the voltage-gated sodium channel Scn1lab (Nav1.lb). ChR2 photostimulation of the putative hindbrain saccade generator was able to fully reconstitute saccades in the didy mutant. Our studies demonstrate that an optogenetic approach is useful for targeted loss-of-function and gain-of-function manipulations of neural circuitry underlying eye movements in zebrafish and that the saccade-generating circuit in this species shares many of its properties with that in mammals.

GABAergic amacrine cells and visual function are reduced in PAC1 transgenic mice.

Pituitary adenylate cyclase activating polypeptide (PACAP) and its high affinity receptor PAC1 are expressed in mammalian retina and involved in processing light information. However, their roles during retinogenesis remain largely elusive. Previously, we have generated transgenic mice overexpressing the human PAC1 receptor, and shown that PACAP signaling is essential for normal development of the central nervous system. In this study, we show for the first time that PACAP signaling plays an important role in the development of retina, particularly in the genesis of GABAergic amacrine cells. Overexpression of the PAC1 receptor leads to an early exit from retinal proliferation, reduced production of GABAergic neurons, and a marked decline in visual function. These data demonstrate that an appropriate level of PACAP signaling is required for normal retinogenesis and visual function. This finding may have implications in GABAergic neuron-related neurological conditions.

Direction-specific disruption of subcortical visual behavior and receptive fields in mice lacking the beta2 subunit of nicotinic acetylcholine receptor.

Retinotopic mapping is a basic feature of visual system organization, but its role in processing visual information is unknown. Mutant mice lacking the beta2 subunit of nicotinic acetylcholine receptor have imprecise maps in both visual cortex (V1) and the superior colliculus (SC) due to the disruption of spontaneous retinal activity during development. Here, we use behavioral and physiological approaches to study their visual functions. We find that beta2-/- mice fail to track visual stimuli moving along the nasotemporal axis in a subcortical optomotor behavior, but track normally along the dorsoventral axis. In contrast, these mice display normal acuity along both axes in the visual water task, a behavioral test of cortical functions. Consistent with the behavioral results, we find that V1 neurons in beta2-/- mice have normal response properties, while SC neurons have disrupted receptive fields, including enlarged structure and decreased direction and orientation selectivity along the nasotemporal axis. The subcortical-specific deficits indicate that retinotopic map disruption has different impacts on the development of functional properties in V1 and the SC.

Distinct roles of transcription factors brn3a and brn3b in controlling the development, morphology, and function of retinal ganglion cells.

Transcriptional regulatory networks that control the morphologic and functional diversity of mammalian neurons are still largely undefined. Here we dissect the roles of the highly homologous POU-domain transcription factors Brn3a and Brn3b in retinal ganglion cell (RGC) development and function using conditional Brn3a and Brn3b alleles that permit the visualization of individual wild-type or mutant cells. We show that Brn3a- and Brn3b-expressing RGCs exhibit overlapping but distinct dendritic stratifications and central projections. Deletion of Brn3a alters dendritic stratification and the ratio of monostratified:bistratified RGCs, with little or no change in central projections. In contrast, deletion of Brn3b leads to RGC transdifferentiation and loss, axon defects in the eye and brain, and defects in central projections that differentially compromise a variety of visually driven behaviors. These findings reveal distinct roles for Brn3a and Brn3b in programming RGC diversity, and they illustrate the broad utility of germline methods for genetically manipulating and visualizing individual identified mammalian neurons.

The optokinetic response in wild type and white zebra finches.

Optic flow is a main source of information about self movement and the three-dimensional composition of the environment during locomotion. It is processed by the accessory optic system in all vertebrates. The optokinetic response is elicited by rotational optic flow, e.g. in a rotating drum lined with vertical stripes. We investigated here the effect of rotational optic flow on the optokinetic response in wild type and white zebra finches. The highest stimulus velocity eliciting an optokinetic response (upper velocity threshold) was dependent on stimulus direction and illumination level, but was not different between the colour morphs. The upper velocity threshold was higher with temporal to nasal movements in monocularly exposed birds and symmetrical with binocular exposure. Its increase with illumination level followed Fechner's law and reached a plateau at about 560 Lux. In bright daylight, white birds did not show optokinetic responses. We conclude that the altered wiring of the visual system of white birds has no influence on accessory optic system function. The unwillingness of white birds to respond with optokinetic response in bright daylight may be due to a substantial lack of inhibition within the visual system as demonstrated earlier, which may enhance the sensibility to glare.

Variation of the response to the optokinetic drum among various strains of mice.

The optokinetic drum has become an appropriate tool to examine visual properties of mice. We performed baseline measurements using mice of the inbred strains C3H, C57BL/6, BALB/c, JF1, 129 and DBA/2 at the age of 8-15 weeks. Each individual C57BL/6, 129 and JF1 mouse was reliably identified as non-affected in vision by determining head-tracking responses. C3H mice were used as negative control because of their inherited retinal degeneration; as expected, they did not respond to the moving stripe pattern. Surprisingly, BALB/c and DBA/2 mice showed the same result. Electroretinography, funduscopy and histology of BALB/c mice did not reveal any abnormality concerning the structure or function of the retina and the remaining eye. Therefore, it might be assumed that BALB/c mice suffer from disturbances of the central visual system. Preliminary results from linkage analysis of the non-responding phenotype in the BALB/c mice indicate a recessive, monogenic mode of inheritance; the causative gene is located on chromosome 7, but significantly different from the albino locus. In conclusion, C57BL/6, 129 and JF1 represent appropriate inbred strains for high throughput screenings with the optokinetic drum.

Oculomotor instabilities in zebrafish mutant belladonna: a behavioral model for congenital nystagmus caused by axonal misrouting.

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.

Cerebellar LTD facilitates but is not essential for long-term adaptation of the vestibulo-ocular reflex.

The induction of cerebellar long-term depression (LTD) at the parallel fibre-Purkinje cell synapse is selectively blocked in L7-PKCi transgenic mice, rendering these mice unable to adaptively modify their vestibulo-ocular reflex (VOR) during visuo-vestibular training for a few hours. Despite this deficit, their eye movement performance as well as their general motor behaviour appears unaffected. This combination suggests that, in the long term, residual forms of plasticity in the vestibulo-cerebellar circuitry can compensate for the absence of cerebellar LTD. To investigate whether LTD-deficient mice exhibit motor learning in the long run, we subjected L7-PKCi transgenic mice to visuo-vestibular training paradigms that were aimed at either increasing or decreasing the VOR response in the course of eight consecutive days. During the increasing paradigm, the VOR gain of transgenic mice increased significantly, while VOR gain decreased and VOR phase-lead increased during the decreasing paradigm. The impact of these long training periods on the VOR was significantly smaller in LTD-deficient mice than in wild type littermates. Thus, while LTD may be necessary for short-term VOR adaptation, it facilitates but is not required for long-term adaptation of the VOR.