Horizontal Optokinetic Response Research Articles

Plastic vasomotion entrainment.

The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel 'shadow' was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse, and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the plastic entrainment of vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions, and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.

Plastic vasomotion entrainment

The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel ‘shadow’ was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse, and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the plastic entrainment of vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions, and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.

Glial modulation of the parallel memory formation.

Actions from glial cells could affect the readiness and efficacy of learning and memory. Using a mouse cerebellar-dependent horizontal optokinetic response motor learning paradigm, short-term memory (STM) formation during the online training period and long-term memory (LTM) formation during the offline rest period were studied. A large variability of online and offline learning efficacies was found. The early bloomers with booming STM often had a suppressed LTM formation and late bloomers with no apparent acute training effect often exhibited boosted offline learning performance. Anion channels containing LRRC8A are known to release glutamate. Conditional knockout of LRRC8A specifically in astrocytes including cerebellar Bergmann glia resulted in a complete loss of STM formation while the LTM formation during the rest period remained. Optogenetic manipulation of glial activity by channelrhodopsin-2 or archaerhodopsin-T (ArchT) during the online training resulted in enhancement or suppression of STM formation, respectively. STM and LTM are likely to be triggered simultaneously during online training, but LTM is expressed later during the offline period. STM appears to be volatile and the achievement during the online training is not handed over to LTM. In addition, we found that glial ArchT photoactivation during the rest period resulted in the augmentation of LTM formation. These data suggest that STM formation and LTM formation are parallel separate processes. Strategies to weigh more on the STM or the LTM could depend on the actions of the glial cells.

Mice lacking EFA6C/Psd2, a guanine nucleotide exchange factor for Arf6, exhibit lower Purkinje cell synaptic density but normal cerebellar motor functions.

ADP ribosylation factor 6 (Arf6) is a small GTPase that regulates various neuronal events including formation of the axon, dendrites and dendritic spines, and synaptic plasticity through actin cytoskeleton remodeling and endosomal trafficking. EFA6C, also known as Psd2, is a guanine nucleotide exchange factor for Arf6 that is preferentially expressed in the cerebellar cortex of adult mice, particularly in Purkinje cells. However, the roles of EFA6C in cerebellar development and functions remain unknown. In this study, we generated global EFA6C knockout (KO) mice using the CRISPR/Cas9 system and investigated their cerebellar phenotypes by histological and behavioral analyses. Histological analyses revealed that EFA6C KO mice exhibited normal gross anatomy of the cerebellar cortex, in terms of the thickness and cellularity of each layer, morphology of Purkinje cells, and distribution patterns of parallel fibers, climbing fibers, and inhibitory synapses. Electron microscopic observation of the cerebellar molecular layer revealed that the density of asymmetric synapses of Purkinje cells was significantly lower in EFA6C KO mice compared with wild-type control mice. However, behavioral analyses using accelerating rotarod and horizontal optokinetic response tests failed to detect any differences in motor coordination, learning or adaptation between the control and EFA6C KO mice. These results suggest that EFA6C plays ancillary roles in cerebellar development and motor functions.

Interneuronal NMDA receptors regulate long-term depression and motor learning in the cerebellum.

NMDA receptors (NMDARs) are required for long-term depression (LTD) at parallel fibre-Purkinje cell synapses, but their cellular localization and physiological functions invivo are unclear. NMDARs in molecular-layer interneurons (MLIs), but not granule cells or Purkinje cells, are required for LTD, but not long-term potentiation induced by low-frequency stimulation of parallel fibres. Nitric oxide produced by NMDAR activation in MLIs probably mediates LTD induction. NMDARs in granule cells or Purkinje cells are dispensable for motor learning during adaptation of horizontal optokinetic responses. Long-term potentiation (LTP) and depression (LTD), which serve as cellular synaptic plasticity models for learning and memory, are crucially regulated by N-methyl-d-aspartate receptors (NMDARs) in various brain regions. In the cerebellum, LTP and LTD at parallel fibre (PF)-Purkinje cell (PC) synapses are thought to mediate certain forms of motor learning. However, while NMDARs are essential for LTD invitro, their cellular localization remains controversial. In addition, whether and how NMDARs mediate motor learning invivo remains unclear. Here, we examined the contribution of NMDARs expressed in granule cells (GCs), PCs and molecular-layer interneurons (MLIs) to LTD/LTP and motor learning by generating GC-, PC- and MLI/PC-specific knockouts of Grin1, a gene encoding an obligatory GluN1 subunit of NMDARs. While robust LTD and LTP were induced at PF-PC synapses in GC- and PC-specific Grin1 (GC-Grin1 and PC-Grin1, respectively) conditional knockout (cKO) mice, only LTD was impaired in MLI/PC-specific Grin1 (MLI/PC-Grin1) cKO mice. Application of diethylamine nitric oxide (NO) sodium, a potent NO donor, to the cerebellar slices restored LTD in MLI/PC-Grin1 cKO mice, suggesting that NO is probably downstream to NMDARs. Furthermore, the adaptation of horizontal optokinetic responses (hOKR), a cerebellar motor learning task, was normally observed in GC-Grin1 cKO and PC-Grin1 cKO mice, but not in MLI/PC-Grin1 cKO mice. These results indicate that it is the NMDARs expressed in MLIs, but not in PCs or GCs, that play important roles in LTD invitro and motor learning invivo.

Optogenetic Control of Synaptic AMPA Receptor Endocytosis Reveals Roles of LTD in Motor Learning

Long-term depression (LTD) of AMPA-type glutamate receptor (AMPA receptor)-mediated synaptic transmission has been proposed as a cellular substrate for learning and memory. Although activity-induced AMPA receptor endocytosis is believed to underlie LTD, it remains largely unclear whether LTD and AMPA receptor endocytosis at specific synapses are causally linked to learning and memory invivo. Here we developed a new optogenetic tool, termed PhotonSABER, which enabled the temporal, spatial, and cell-type-specific control of AMPA receptor endocytosis at active synapses, while the basal synaptic properties and other forms of synaptic plasticity were unaffected. We found that fiberoptic illumination to Purkinje cells expressing PhotonSABER invivo inhibited cerebellar motor learning during adaptation of the horizontal optokinetic response and vestibulo-ocular reflex, as well assynaptic AMPA receptor decrease in the flocculus. Our results demonstrate that LTD and AMPA receptor endocytosis at specific neuronal circuits were directly responsible for motor learning invivo. VIDEO ABSTRACT.

Loss of GPRC5B impairs synapse formation of Purkinje cells with cerebellar nuclear neurons and disrupts cerebellar synaptic plasticity and motor learning

GPRC5B is a membrane glycoprotein robustly expressed in mouse cerebellar Purkinje cells (PCs). Its function is unknown. In Gprc5b−/− mice that lack GPRC5B, PCs develop distal axonal swellings in deep cerebellar nuclei (DCN). Numerous misshapen mitochondria, which generated excessive amounts of reactive oxygen species (ROS), accumulated in these distal axonal swellings. In primary cell cultures of Gprc5b−/− PCs, pharmacological reduction of ROS prevented the appearance of such swellings. To examine the physiological role of GPRC5B in PCs, we analyzed cerebellar synaptic transmission and cerebellum-dependent motor learning in Gprc5b−/− mice. Patch-clamp recordings in cerebellum slices in vitro revealed that the induction of long-term depression (LTD) at parallel fiber-PC synapses was normal in adult Gprc5b−/− mice, whereas the induction of long-term potentiation (LTP) at mossy fiber-DCN neuron synapses was attenuated in juvenile Gprc5b−/− mice. In Gprc5b−/− mice, long-term motor learning was impaired in both the rotarod test and the horizontal optokinetic response eye movement (HOKR) test. These observations suggest that GPRC5B plays not only an important role in the development of distal axons of PCs and formation of synapses with DCN neurons, but also in the synaptic plasticity that underlies long-term motor learning.

Motor learning in common marmosets: Vestibulo-ocular reflex adaptation and its sensitivity to inhibitors of Purkinje cell long-term depression

Adaptation of the horizontal vestibulo-ocular reflex (HVOR) provides an experimental model for cerebellum-dependent motor learning. We developed an eye movement measuring system and a paradigm for induction of HVOR adaptation for the common marmoset. The HVOR gain in dark measured by 10° (peak-to-peak amplitude) and 0.11–0.5Hz turntable oscillation was around unity. The gain-up and gain-down HVOR adaptation was induced by 1h of sustained out-of-phase and in-phase 10°–0.33Hz combined turntable-screen oscillation in the light, respectively. To examine the role of long-term depression (LTD) of parallel fiber-Purkinje cell synapses, we intraperitonially applied T-588 or nimesulide, which block the induction of LTD in vitro or in vivo preparations, 1h before the test of HVOR adaptation. T-588 (3 and 5mg/kg body weight) did not affect nonadapted HVOR gains, and impaired both gain-up and gain-down HVOR adaptation. Nimesulide (3 and 6mg/kg) did not affect nonadapted HVOR gains, and impaired gain-up HVOR adaptation dose-dependently; however, it very little affected gain-down HVOR adaptation. These findings are consistent with the results of our study of nimesulide on the adaptation of horizontal optokinetic response in mice (Le et al., 2010), and support the view that LTD underlies HVOR adaptation.

Distinct cerebellar engrams in short-term and long-term motor learning

Cerebellar motor learning is suggested to be caused by long-term plasticity of excitatory parallel fiber-Purkinje cell (PF-PC) synapses associated with changes in the number of synaptic AMPA-type glutamate receptors (AMPARs). However, whether the AMPARs decrease or increase in individual PF-PC synapses occurs in physiological motor learning and accounts for memory that lasts over days remains elusive. We combined quantitative SDS-digested freeze-fracture replica labeling for AMPAR and physical dissector electron microscopy with a simple model of cerebellar motor learning, adaptation of horizontal optokinetic response (HOKR) in mouse. After 1-h training of HOKR, short-term adaptation (STA) was accompanied with transient decrease in AMPARs by 28% in target PF-PC synapses. STA was well correlated with AMPAR decrease in individual animals and both STA and AMPAR decrease recovered to basal levels within 24 h. Surprisingly, long-term adaptation (LTA) after five consecutive daily trainings of 1-h HOKR did not alter the number of AMPARs in PF-PC synapses but caused gradual and persistent synapse elimination by 45%, with corresponding PC spine loss by the fifth training day. Furthermore, recovery of LTA after 2 wk was well correlated with increase of PF-PC synapses to the control level. Our findings indicate that the AMPARs decrease in PF-PC synapses and the elimination of these synapses are in vivo engrams in short- and long-term motor learning, respectively, showing a unique type of synaptic plasticity that may contribute to memory consolidation.

The Optokinetic Uncover Test

We devised the optokinetic uncover test to examine the role of peripheral retinal motion input in generating horizontal optokinetic responses in patients with infantile strabismus. To ascertain whether subcortical visual input contributes to the asymmetrical monocular optokinetic responses that characterize infantile esotropia. Observational study in an academic research setting. Ten patients with infantile esotropia. Optokinetic uncover test. Optokinetic testing was performed in 7 patients with isolated infantile esotropia (5 untreated and 2 previously treated) and in 3 patients with infantile esotropia syndrome associated with mild neurological disease. RESULTS All patients showed poor temporally directed optokinetic responses that instantaneously improved when the occluded esodeviated eye was uncovered, exposing it to nasally directed optokinetic motion. This improvement in optokinetic responses did not necessitate a fixation shift to the contralateral eye. Nasally directed optokinetic input to the esodeviated eye can supplement temporal monocular optokinetic responses in the fixating eye under binocular conditions. This nonfoveal optokinetic contribution suggests that monocular nasotemporal optokinetic asymmetry is partly attributable to subcortical visuovestibular responses mediated by nonfoveal retina.

Post-training cerebellar cortical activity plays an important role for consolidation of memory of cerebellum-dependent motor learning

Adaptation of mouse horizontal optokinetic response (HOKR) eye movement provides an experimental model for cerebellum-dependent motor learning. Our previous study revealed that the memory trace of HOKR adaptation is initially encoded in the cerebellar flocculus after hours of optokinetic training, and transferred to the vestibular nuclei to be consolidated to long-term motor memory after days of training [28]. To reveal how the cerebellar cortex operates in the transfer of the memory trace of adaptation, we examined the effects of shutdown of the cerebellar cortex after daily training. Three groups of mice received 1 h of optokinetic training daily for 4 days, and showed similar amounts of adaptation after the end of 1 h of training throughout 4 days. However, in the mice which daily received bilateral floccular muscimol infusion under gas anesthesia in the post-training period, consolidation of memory of the adaptation was markedly impaired, compared with the control mice which daily received bilateral floccular Ringer's solution infusions under gas anesthesia or those which daily received only gas anesthesia. These results are consistent with the studies of the effects of inactivation of cerebellar cortex on the consolidation of motor memory of rabbit eyeblink conditioning [2,4,18], and suggest that the post-training cerebellar cortex activity play an important for the consolidation of motor memory of HOKR adaptation.

Role of Cerebellar Cortical Protein Synthesis in Transfer of Memory Trace of Cerebellum-Dependent Motor Learning

We developed a new protocol that induces long-term adaptation of horizontal optokinetic response (HOKR) eye movement by hours of spaced training and examined the role of protein synthesis in the cerebellar cortex in the formation of memory of adaptation. Mice were trained to view 800 cycles of screen oscillation either by 1 h of massed training or by 2.5 h to 8 d of training with 0.5 h to 1 d space intervals. The HOKR gains increased similarly by 20-30% at the end of training; however, the gains increased by 1 h of massed training recovered within 24 h, whereas the gains increased by spaced training were sustained over 24 h. Bilateral floccular lidocaine microinfusions immediately after the end of training recovered the gains increased by 1 h of massed training but did not affect the gains increased by 4 h of spaced training, suggesting that the memory trace of adaptation was transferred from the flocculus to the vestibular nuclei within 4 h of spaced training. Blockade of floccular protein synthesis, examined by bilateral floccular microinfusions of anisomycin or actinomycin D 1-4 h before the training, impaired the gains increased by 4 h of spaced training but did not affect the gains increased by 1 h of massed training. These findings suggest that the transfer of the memory trace of adaptation occurs within 4 h of spaced training, and proteins synthesized in the flocculus during training period may play an important role in memory transfer.

Structural changes at parallel fibre to Purkinje cell synapses after long-term adaptation of horizontal optokinetic response

Structural changes at parallel fibre to Purkinje cell synapses after long-term adaptation of horizontal optokinetic response

Memory trace of motor learning shifts transsynaptically from cerebellar cortex to nuclei for consolidation

Adaptation of ocular reflexes is a prototype of motor learning. While the cerebellum is acknowledged as the critical site for motor learning, the functional differences between the cerebellar cortex and nuclei in motor memory formation are not precisely known. Two different views are proposed: one that the memory is formed within the cerebellar flocculus, and the other that the memory is formed within vestibular nuclei. Here we developed a new paradigm of long-term adaptation of mouse horizontal optokinetic response eye movements and examined the location of its memory trace. We also tested the role of flocculus and inferior olive in long-term adaptation by chronic lesion experiments. Reversible bilateral flocculus shutdown with local application of 0.5 μl–5% lidocaine extinguished the memory trace of day-long adaptation, while it very little affected the memory trace of week-long adaptation. The responsiveness of vestibular nuclei after week-long adaptation was examined by measuring the extracellular field responses to the electrical stimulation of vestibular nerve under trichloroacetaldehyde anesthesia. The amplitudes and slopes of evoked monosynaptic field response (N 1) of week-long adapted mice were enhanced around the medial vestibular nucleus compared with those of control mice. Chronic flocculus or inferior olive lesions abolished both day and week-long adaptations. These results suggest that the functional memory trace of short-term adaptation is formed initially within the cerebellar cortex, and later transferred to vestibular nuclei to be consolidated to a long-term memory. Both day and week-long adaptations were markedly depressed when neural nitric oxide was pharmacologically blocked locally and when neuronal nitric oxide synthase was ablated by gene knockout, suggesting that cerebellar long-term depression underlies both acquisition and consolidation of motor memory.

Eye movements of the murine P/Q calcium channel mutant rocker, and the impact of aging.

Mutations in the gene encoding the ion pore of the P/Q voltage-activated calcium channel (CACNA1A) are predicted to alter synaptic transmission and dendritic excitability within cerebellar granule and Purkinje cells. Determining the relationships between these alterations, neuronal activity, and behavior may yield insight into the relationship between neuronal intrinsic properties and signal processing within the ocular motor system. Toward this end, we compared ocular motor performance in the CACNA1A mutant rocker and C57BL/6 controls. Average vertical eye position was abnormally elevated in the mutants, a finding that may be analogous to downbeat nystagmus seen in human cerebellar disorders. Fast phases of vestibular nystagmus were slowed by approximately 18% of control values. The angular vestibuloocular reflex (VOR) in darkness and light (visual VOR, or VVOR), assessed at 0.1-1.6 Hz, exhibited subnormal gains at the highest stimulus frequencies and increased phase leads at the lowest stimulus frequencies. Horizontal optokinetic responses to constant velocity drum rotation of +/-2.5-40 degrees/s exhibited minimally reduced gains. Attempts to increase VOR gain by concomitant optokinetic and vestibular stimulation were confounded by the tendency of the mice to habituate to repetitive vestibular stimulation, but attempts to induce coupling of vertical eye movements to horizontal vestibular stimulation (cross-axis adaptation) generated rapid plastic changes in controls and little effect in mutants. With the notable exceptions of the vertical elevation and optokinetic gains, the ocular motor abnormalities were stable over a broad range of animal age, a result compatible with the abnormalities arising as direct consequences of the inborn alteration in calcium channel biophysics.

Role of protein kinase C family in the cerebellum-dependent adaptive learning of horizontal optokinetic response eye movements in mice.

Among the subtypes of the Ca2+-dependent protein kinase C (PKC), which play a crucial role in long-term depression (LTD), both alpha and gamma are expressed in the cerebellar floccular Purkinje cells. To reveal the functional differences of PKC subtypes, we examined the adaptability of ocular reflexes of PKCgamma mutant mice, which show mild ataxia and normal LTD. In mutant mice, gains of the horizontal optokinetic eye response (HOKR) were reduced. Adaptation of the HOKR was not affected but its retinal slip dependency was altered in mutant mice. Sustained 1-h sinusoidal screen oscillation, which induced a relatively large amount of retinal slips in both mutant and wild-type mice, increased the HOKR gain in wild-type mice but not in mutant mice. In contrast, exposure to 1 h of sustained slower screen oscillations, which induced relatively small retinal slips in mutant and wild-type mice, increased the HOKR gain in both mutant and wild-type mice. Adaptation of the HOKR of the mutant mice to slow screen oscillation and those of wild-type mice to fast and slow screen oscillations were all abolished by local applications of a PKC inhibitor (chelerythrine) within the flocculi. Electrophysiological and anatomical studies showed no appreciable changes in the sources and magnitudes of climbing fibre inputs, which mediate retinal slip signals to the flocculus in the mutant mice. These results suggest that PKCgamma has a modulatory role in determining retinal slip dependency, and other PKC subtypes, e.g. PKCalpha, may play a crucial role in the adaptation of the HOKR.

Disorders of vertical optokinetic nystagmus in patients with ocular misalignment

Purpose. To compare responses to vertical and horizontal optokinetic (OK) stimulation in patients with disorders of ocular alignment. Methods. Using the magnetic search coil technique, we measured horizontal and vertical rotations of both eyes in six patients with strabismus since childhood and eight normal subjects. The OK stimulus subtended 72° horizontally and 60° vertically, consisted of black-and-white stripes with a spatial frequency of 0.04 cycles/degree, and moved either vertically or horizontally at 22.5 or 12°/s. All patients and controls were tested with both eyes viewing and monocularly. Results. Vertical OK responses were asymmetric in most normals and patients. The direction of this asymmetry varied between individuals, but upward stimuli more commonly elicited a greater response than downward stimuli. Monocular horizontal OK responses were symmetric in normals; patients showed either an asymmetry with greater responses for nasal motion, or a directional bias. During monocular and binocular viewing, vertical OK stimulation induced vertical nystagmus in normal subjects, but all patients showed diagonal responses, with horizontal components that were significantly greater than controls. The inappropriate horizontal component of the response increased at the higher stimulus speed, and was not simply due to latent nystagmus. Conclusions. Patients with disorders of ocular alignment since childhood show an inappropriate horizontal response to vertical OK stimuli, indicating directional abnormality of either motion vision pathways or the ocular motor response.

Video-oculography in the gerbil

Normative vestibulo-ocular and optokinetic reflexes (VOR and OKR) and pupil diameter were measured in young adult gerbils using infrared video-oculography with 60 Hz sampling during head-fixed binocular recordings. The pupillary light-sink technique was preferred over a single-beam retinal reflection method because its measurements were less affected by pupil size. Eye movements were generally conjugate with occasional independent saccadic movements, and independent drifting movements in the dark. The horizontal optokinetic response to sinusoidal motion of a randomly spaced white dot pattern was maximal at low velocities (5°/s), stronger temporonasally, and dropped off quickly at ∼20°/s. Constant velocity gain was near unity through 60–80°/s with a sharp drop-off. Monocular viewing revealed almost no nasotemporal optokinetic response. Pupil diameter was found to vary as a saddle function with optokinetic gain from cycle to cycle, but also have a circadian rhythm (smaller at dusk) that related inversely to mean horizontal VOR gain. Gerbils with eyes open sometimes had no optokinetic response during long stimulus periods, which then resumed after a brief vestibular stimulus. The horizontal angular VOR gain was relatively flat across 0.1–1.0 Hz and 30–120 d/s sines (phase near zero), with a mean gain of ∼0.78 in the dark, and 1.0 with the fixed pattern surround ( n=15, for both raw calibrated and normalized data). Most animals also revealed a strong slow phase eye velocity asymmetry (dominant during ipsilateral rotation) in the half-cycle gain of their horizontal angular VOR response in the dark. A constant velocity horizontal optokinetic bias velocity did not change the gain or symmetry of the sinusoidal VOR response, but shifted the VOR response velocity in an additive (linear) fashion. Both cross-coupling (pitch or roll while rotating) and pseudo-OVAR (off-axis counter-rotation) stimuli generated horizontal nystagmus. The findings suggest that the gerbil, like other lateral-eyed rodents, relies on otolith cues to interpret angular motion.

Loss of adaptability of horizontal optokinetic response eye movements in mGluR1 knockout mice.

Metabotropic glutamate receptor subtype 1 (mGluR1) plays an essential role in the cerebellar long-term depression (LTD). We examined the dynamic characteristics and adaptability of horizontal vestibulo-ocular reflex (HVOR) and optokinetic response (HOKR) eye movements in mGluR1 knockout mice. A mild difference was seen in the HOKR/HVOR dynamics between the wild-type and mGluR1(-/-) mice. Exposure to 1 h of sustained screen oscillation, which induced HOKR adaptation in wild-type mice, induced no change in mutant mice. These results suggest that the mGluR1 plays an essential role in the adaptation of HOKR, and LTD underlies the adaptation of ocular reflexes.

Inhibition of nitric oxide synthesis and gene knockout of neuronal nitric oxide synthase impaired adaptation of mouse optokinetic response eye movements.

Nitric oxide (NO) plays a key role in synaptic transmission efficiency in the central nervous system. To gain an insight on the role of NO in cerebellar functions, we, here, measured the dynamics of the horizontal optokinetic response (HOKR) and vestibulo-ocular reflex (HVOR), and the adaptation of HOKR in mice locally injected with N(G)-monomethyl-L-arginine (L-NMMA) that inhibits NO synthesis and in mice devoid of neuronal nitric oxide synthase (nNOS). Local application of L-NMMA into the cerebellar flocculi induced no change in the dynamics of the HOKR but markedly depressed the adaptation of the HOKR induced by 1 hr of sustained screen oscillation. A slight difference was seen in the HOKR but not in the HVOR dynamics between nNOS(-/-) mutant and wild-type mice. One hour of sustained screen oscillation induced adaptation of the HOKR gains in wild-type mice but not in mutants. These observations suggest that NO is essential for the adaptation of the HOKR and that nNOS is the major enzyme for NO synthesis in the process.