Voltage-gated sodium channels in cerebellar Purkinje cells of mormyrid fish.

Cerebellar Purkinje cells of mormyrid fish differ in some morphological as well as physiological parameters from their counterparts in mammals. Morphologically, Purkinje cells of mormyrids have larger dendrites that are characterized by a lower degree of branching in the molecular layer. Physiologically, there are differences in electrophysiological response patterns that are related to sodium channel activity: first, sodium spikes in mormyrid Purkinje cells have low amplitudes, typically not exceeding 30 mV. Second, the response to climbing fiber stimulation in mormyrid Purkinje cells does not consist of a complex spike (with an initial fast sodium spike) as in mammals, but instead it consists of an all-or-none excitatory postsynaptic potential, the so-called climbing fiber response. Because of these unique properties, we have begun to characterize mormyrid Purkinje cells electrophysiologically. In this study, we provide a description of voltage-gated Na+ channels and conductances in Purkinje cells of the mormyrid fish Gnathonemus petersii. Various types of Na+ channel alpha-subunits, i.e., Nav1.1, Nav1.2, and Nav1.6, have been described in rodent Purkinje cells. Using immunohistochemical techniques, we found that these subunits are present in Purkinje cells of mormyrids. To test whether these Na+ channel subunits can mediate fast inactivating and resurgent Na+ currents in Gnathonemus Purkinje cells, we conducted patch-clamp recordings in acutely dissociated cells and in cerebellar slices. Both types of Na+ currents could be measured in rat and fish Purkinje cells. These data show that, despite prominent differences in electrophysiological response characteristics, Purkinje cells of rats and mormyrids share the same voltage-gated Na+ conductances.

Otolith deprivation induces optokinetic compensation.

According to the multisensory integration theory vestibular, optokinetic and proprioceptive inputs act in concert to maintain a stable retinal image of the visual world. Yet, it remains elusive to what extent the otolith organs contribute to this process and whether a specific loss of otolith input is compensated for. Here we investigated the compensatory eye movements in tilted mice, which lack otoconia because of a mutation in otopetrin 1. Tilted mice showed very small displacements of the eyes in the orbit during static roll paradigms, suggesting the absence of functional otolith organs. Independent of head position with respect to gravity, the gain and phase lead of angular vestibuloocular reflex of tilted mice were decreased and increased, respectively (frequencies 0.2 to 1 Hz and peak accelerations 8 to 197 degrees /s2, respectively). Furthermore, lack of otolith input increases the dependency of the vestibular system on stimulus frequency. In contrast, the gain of optokinetic reflex in tilted mice was significantly higher in the low-frequency range than in control mice, regardless of the position of the mice in space or the plane of the eye movements. To explain these results, a simple model was used in which a multisensory integration unit was embedded. With this model, we were able to simulate all the behaviors observed. Thus our data and the model support the presence of the multisensory integration system and revealed a compensatory enhanced optokinetic reflex in tilted mice, indicating an adaptive synergism in the processing of otolith and visually driven signals.

Hearing loss in infantile Pompe's disease and determination of underlying pathology in the knockout mouse.

Hearing deficit occurs in several lysosomal storage disorders but has so far not been recognized as a symptom of Pompe's disease (glycogen storage disease type II). We discovered quite unexpectedly 30-90 dB hearing loss in four infants with Pompe's disease, who participated in a study on the safety and efficacy of enzyme replacement therapy. Three other patients with juvenile Pompe's disease did not have this symptom. The ABR (auditory brainstem response) thresholds but not the interpeak latency times were increased. This pointed to middle or inner ear pathology rather than to involvement of the central auditory nervous system. The possible occurrence of cochlear pathology was supported by the absence of oto-acoustic emissions. We investigated this hypothesis in a knockout mouse model of Pompe's disease and found glycogen storage in the inner and outer hair cells of the cochlea, the supporting cells, the stria vascularis, and the spiral ganglion cells. We conclude that cochlear pathology is the most likely cause of hearing loss in infantile Pompe's disease and possibly a characteristic feature of this clinical subtype.