Volume 20, Issue 3

Giant synapses in the central auditory system. Giant synapses occur in four nuclei of the auditory brainstem. They are characterized by numerous active zones concentrated on the soma of the postsynaptic neuron and by rapid postsynaptic currents. At these sites, in the ventral cochlear nucleus, the medial and lateral nucleus of the trapezoid body and the ventral nucleus of the lateral lemniscus, faithful preservation of the temporal relation of action potentials to the sound - inter­cellular precision - is of uttermost importance for neuronal function. The precision of action potential transfer is supported by the largely unimodal integration and by the homogeneity of the single postsynaptic compartment. Due to the much more rapid time constant of the synaptic currents compared to the membrane time constant, membrane capacitance dominates postsynaptic integration, enhancing precision of action potential generation. Taken together, the properties of these giant synapses reduce the temporal jitter of the transmission of information in these auditory circuits.

The voltage-activated L-type calcium channels Ca v 1.2 and Ca v 1.3 mediate Ca 2+ influx into neurons at the soma or at dendrites, whereas they are not observed at the presynapse. Surprisingly, in the inner ear, Ca v 1.3 is indispensable for signal transmission from the cochlear inner hair cells to the postsynaptic auditory nerve fibers. Due to Ca v 1.3 channel clustering at ribbons, i.e. specific presynaptic structures of the hair cells, they promote Ca 2+ influx which triggers calcium-dependent fusion of synaptic vesicles with the plasma membrane. Consequently, mutations in Cacna1d, the gene that encodes Ca v 1.3, cause deafness. Additionally, Ca v 1.3 plays an important part in the central auditory system. Lack of the channel results in severe changes in auditory pathway cytoarchitecture and in abnormal electrophysiological performance of auditory neurons. Furthermore, deve­lopmental refinement of tonotopic inhibitory projections in sound localization circuits is disrupted. These aberrations are associated with abnormal sound processing in the auditory pathway. Cacna1d therefore represents a prototypal deafness associated gene, in which mutations result in both peripheral and central auditory deficiencies. This, in turn, has implications for auditory rehabilitation using cochlear implants which address only peripheral dysfunctions. Exploratory research into the closely related Ca v 1.2 isoform points to an important role of this channel in acoustic trauma. Ca v 1.2 is mainly expressed in the auditory nerve, but apparently not essential for normal auditory function. Rather, loss of function of the channel does influence the effects of traumatic noise exposure. Loss of this channel induced by noise trauma results in reduced auditory threshold increase. This phenomenon points to the fact that Ca v 1.2-mediated Ca 2+ influx is involved in noise trauma induced damage. Deeper insight into this function might result in new therapeutic approaches.

Hereditary hearing loss in humans - the importance of genetic approaches for clinical medicine and basic science Hereditary hearing loss belongs to the most common monogenic diseases in humans and, depending on the severity of symptoms and age of onset, the dysfunction of one of the main sensory systems can lead to major problems for the affected individual and his/her social environment. The diagnostic workup of hearing impairment is com­plicated by a pronounced phenotypic variability and extensive genetic heterogeneity. Nevertheless, many forms of monogenic hearing impairment have been elucidated during the last years by genetic approaches. In addition to improved counseling and medical management of patients and families, these scientific results have contributed significantly to the identification of functionally relevant molecules of the inner ear and have thus helped to better understand the molecular physiology of hearing and pathophysiology of hearing impairment.

Drosophila hearing: mechanisms and genes. The fruit fly Drosophila melanogaster communicates acoustically and hears with its antennae. Fundamental aspects of hearing can be studied in these antennal ears. Their auditory sensory cells are evolutionarily related with vertebrate hair cells and are developmentally specified by homologous transcription factors. Like vertebrate hair cells, Drosophila auditory sensory cells are also motile and actively amplify the mechanical vibrations that they transduce. This transduction and amplification rely on the interplay between mechanically activated ion channels and motor proteins, whose movement impacts on the macroscopic performance of the ear. First molecular trans­ducer components have been identified and various auditory relevant proteins have been described. Several of these proteins are conserved components of cilia, putting forward the fly’s ear as a model for human ciliopathies. Also the evolution of sensory signalling cascades can be studied using the fly’s ear as the fly employs key Chemo-and Photoreceptor proteins to hear. Evidence is also accumulating that the fly’s ear is a multifunctional sensory organ that, in addition to mediating hearing, serves the detection of wind and gravity and, presumably, temperature.

Giant synapses occur in four nuclei of the au­ditory brainstem. They are characterized by numerous active zones concentrated on the soma of the postsynaptic neuron and by rap­id postsynaptic currents. At these sites, in the ventral cochlear nucleus, the medial and lat­eral nucleus of the trapezoid body and the ventral nucleus of the lateral lemniscus, faith­ful preservation of the temporal relation of action potentials to the sound-intercellu­lar precision-is of the utmost importance for neuronal function. The precision of action potential transfer is supported by the large­ly unimodal integration and homogeneity of the single postsynaptic compartment. Due to the much more rapid time constant of the synaptic currents compared with the mem­brane time constant, membrane capacitance dominates postsynaptic integration, enhanc­ing precision of action potential generation. Taken together, the properties of these gi­ant synapses reduce the temporal jitter of the transmission of information in these audito­ry circuits.

The voltage-activated L-type calcium chan­nels Cav1.2 and Cav1.3 mediate Ca 2+ influx into neurons at the soma or at dendrites, whereas they are not observed at the pre­synapse. Surprisingly, in the inner ear, Cav1.3 is indispensable for signal transmission from the presynaptic cochlear inner hair cells to the postsynaptic auditory nerve fibers. Due to Cav1.3 channel clustering at ribbons, i.e., specific presynaptic structures of the hair cells, they promote Ca 2+ influx, which triggers calcium-dependent fusion of synaptic vesi­cles with the plasma membrane. Mutations in Cacna1d, a gene that encodes Cav1.3, re­sult in deafness because release of the neu­rotransmitter glutamate at the synapses is abolished. Moreover, studies of the auditory pathway have revealed that Cav1.3 plays an important part in the central auditory system as well. Absence of the channel results in se­vere changes in auditory pathway cytoarchi­tecture and in abnormal electrophysiological performance of auditory neurons. Further­more, developmental refinement of tonotop­ic inhibitory projections in sound localization circuits is disrupted. These aberrations are as­sociated with abnormal sound processing in the auditory pathway. This goes to show that the Cav1.3 channel is essential for in­ner ear functioning as well as auditory path­way development and performance. Cac­na1d therefore represents a prototypal deaf­ness-associated gene, in which mutations re­sult in both peripheral and central audito­ry deficiencies. This, in turn, has implications for auditory rehabilitation using cochlear im­plants that address only peripheral dysfunc­tions. Exploratory research into the closely re­lated Cav1.2 isoform points to an important role of this channel in acoustic trauma. Cav1.2 is mainly expressed in the auditory nerve, but apparently not essential for normal audito­ry function. Loss of function of the channel, however, does influence the effects of trau­matic noise exposure. Loss of this channel in­duced by noise trauma results in reduced au­ditory threshold increase-as compared with the control group. This phenomenon points to the fact that Cav1.2-mediated Ca 2+ influx is involved in noise trauma-induced damage. Deeper insight into this function might result in new therapeutic approaches.

Hereditary hearing loss is one of the most common monogenic diseases in humans and, depending on the severity of symptoms and age of onset, dysfunction of one of the main sensory systems can cause significant problems for the affected individual and his/her social environment. The diagnostic work­up of hearing impairment is complicated by a pronounced phenotypic variability and ex­tensive genetic heterogeneity. Nevertheless, many forms of monogenic hearing impair­ment have been elucidated in recent years by genetic approaches. In addition to improved counselling and medical management of pa­tients and families, these research findings have contributed significantly to the identi­fication of functionally relevant molecules of the inner ear and have thus helped us to bet­ter understand the molecular physiology of hearing and the pathophysiology of hearing impairment.

The fruit fly Drosophila melanogaster com­municates acoustically and hears with its an­tennae. Fundamental aspects of hearing can be studied in these antennal ears, the audi­tory sensory cells of which are evolutionarily related to vertebrate hair cells and are spec­ified developmentally by homologous tran­scription factors. Like vertebrate hair cells, Drosophila auditory sensory cells are also mo­tile and actively amplify the mechanical vi­brations they transduce. The transduction and amplification mechanisms rely on the in­terplay between mechanically activated ion channels and motor proteins, whose move­ment impacts upon the macroscopic perfor­mance of the ear. The first molecular trans­ducer components have been identified and various auditory system-relevant proteins have been described. Several of these pro­teins are conserved components of cilia, sug­gesting the fly’s ear as a model for human cil­iopathies. The evolution of sensory signaling cascades can also be studied using the fly’s ear, as the fly employs key chemo- and pho­toreceptor proteins to hear. Evidence is al­so accumulating that the fly’s ear is a multi­functional sensory organ, which, in addition to mediating hearing, serves to detect wind, gravity and presumably temperature.