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Max-Planck-Institut für Experimentelle Medizin
Group Leaders: Tobias Moser, Carolin Wichmann, Tina Pangršic Vilfan

Auditory Neuroscience

We study the molecular physiology, pathophysiology and restoration of hearing and balance. We aim to elucidate the specialized molecular and cellular mechanisms that enable indefatigable synaptic encoding and transmission of sensory information with submillisecond temporal precision at hundreds per second over hours. We combine complementary approaches to dissect the structure and function of hair cell ribbon synapses in the cochlea and of calyceal synapses of the central auditory system. Moreover, we work towards the restoration of hearing using gene-therapeutic and optogenetic approaches.

Molecular anatomy, physiology and pathology of synaptic encoding and processing of sensory information

The hair cell synapse features a single and “large” ribbon-type active zone with approximately one dozen release sites and tens of voltage-gated Ca2+ channels. When hair cells transduce a sound driven mechanical stimulus into an electrical signal, Ca2+ channels open and the Ca2+ influx triggers exocytosis of glutamate filled vesicles at the ribbon synapses. Our work on the hair cell ribbon aims at a comprehensive understanding of synaptic encoding. It follows three main avenues: the dissection of molecular anatomy and physiology, elucidation of the mechanism(s) of release and the control by Ca2+ channels, and the vesicle cycling at the active zone. The large calyceal synapses of the central auditory pathway are specialized in high throughput synaptic transmission, capable of sustaining signaling frequencies of several hundreds of Hertz. The endbulb and calyx of Held synapses employ hundred(s) of “small“ active zones that act in parallel driving massive excitation of the principal cells of the cochlear nucleus and the medial nucleus of the trapezoid from large presynaptic terminals that contact a substantial fraction of the postsynaptic soma.
The molecular composition of these auditory synapses is only becoming elucidated but clearly differs between both synapse types. The hair cell synapse seems to operate with an unconventional molecular machinery, on which much was learned from human genetics analysis of deafness and candidate approaches testing for the function of proteins with important roles at conventional synapses of the central nervous tissue. While the former have identified important players such as the C2 domain protein otoferlin and the hair cell-specific Ca2+ channel complex, the latter have often failed to detect functional expression of key molecules such as neuronal SNAREs, synaptotagmin 1 and complexin. However, some of the proteins such as the presynaptic scaffold protein bassoon are required for both synapses and hearing.

Synaptic encoding and processing of sensory information in the inner ear
Left: the lower auditory pathway with ribbon synapse between inner hair cell (IHC) and spiral ganglion neurons (SGN) and central auditory synapses in the cochlear nucleus (CN) and medial nucleus of the trapezoid body (MNTB) of the brainstem.  Right: schematic representations of (A) the calyceal synapses of the central auditory pathway: many small active zones and (B) of the hair cell ribbon synapse (only one of 5-20 synapses per hair cell drawn for clarity): single active zone per postsynaptic neuron.

Ribbon synapses in the inner ear
Left: immunohistochemical staining of inner hair cell nuclei and ribbon synapses (red) and the postsynaptic GluA2/3 glutamate receptors (green) overlaid on a phase contract picture showing the stereocilia (gray). The outline of one inner hair cell is shown in white and orange lines indicate the 1:1 connections of presynaptic active zones to individual spiral ganglion neurons. Right: The molecular composition of inner hair cell ribbon synapses is tightly organized by scaffolding proteins such as bassoon, RIM, and ribeye.

Calcium signaling at the inner hair cell ribbon synapse
Left: representative depolarization-evoked Ca2+ domains at individual active zones show the heterogeneity of responses found in inner hair cells. Right: the proposed nanodomain organization of inner hair cell active zones results in linear dependence of vesicular release on Ca2+ influx when changing the number of open channels but supralinear dependence when changing the single channel current.

Electrophysiological recordings from endbulb of Held synapses in the central nervous system
Left: a bushy cell in a slice preparation targeted by a patch-clamp pipette coming from the right. Middle: schematic representation of double-patch experiments where electrophysiological measurements are undertaken at both the presynaptic endbulb of Held and the postsynaptic soma of the bushy cell. Right: immunohistochemical staining of a bushy cell showing calretinin labeling an endbulb of Held (green) and bassoon indicating smaller excitatory and inhibitory synapses (magenta).

Restoration of hearing

Approximately 360 million people – 5% of the world’s population – suffer from disabling hearing impairment (HI), commonly causing social isolation, depression, and reduction in professional capabilities. So far despite major research efforts, a causal treatment based on pharmacology, gene therapy or stem cells is not yet available for its most common form: sensorineural HI. One of our efforts is towards development of gene therapy for monogenic deafness, such as DNFB93 using replacement of the defective CABP2 gene via adeno-associated virus. Hearing aids and auditory implants, cochlear implants (CIs) and auditory brainstem implants (ABIs), represent the state-of-the-art approaches for partial restoration of auditory function and they are likely to remain key means for alleviating sensorineural HI also during the coming decades. The cochlear implant, used worldwide by more than 300.000 hearing impaired people, typically enables open speech understanding and is considered the most successful neuroprosthesis. Nonetheless, listening in noisy environments as well as music appreciation remain challenging mostly because of the poor frequency and intensity resolution that results from broad current spread from of each of the 1-2 dozens of electrode contacts. Since light can be conveniently focused, optogenetic stimulation of the spiral ganglion of the cochlea promises a fundamental improvement of frequency and intensity coding compared to that achievable with electrical cochlear implants. This principle involves the expression of light-sensitive ion channels, so called channelrhodopsins such as ChR2, in the neurons in order to render them light-sensitive. Placing linear emitter arrays into the cochlea one might be enable true multichannel stimulation with tens of independent information channels to the neurons.

Optogenetic stimulation of the auditory pathway “Cochlear Optogenetics”
Left: In electrical CIs usually 8-24 electrode contacts (blue or red) are used to stimulate spiral ganglion neurons by charge-neutral biphasic stimuli in a monopolar configuration (red contacts). Current spread leads to activation of a large population of neurons along the spiral tonotopic axis by any active contact (blue halo), thereby limiting the frequency resolution of electrical coding.
Right: optical stimulation e.g. light emitted from microscale light emitting diodes (µLEDs) focused by lenses or emitted from waveguide arrays promises spatially confined activation of spiral ganglion neurons allowing for a higher number of independent stimulation channels and improving the frequency and intensity resolution of sound coding.

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