Behavioral Neuroscience publications

Hair cells of the inner ear and lateral-line system rely on specialized ribbon synapses to transmit sensory information to the central nervous system. The molecules required to assemble these synapses are not fully understood. We show that Nrxn3, a presynaptic adhesion molecule, is crucial for ribbon-synapse maturation in hair cells. In both mouse and zebrafish models, the loss of Nrxn3 results in significantly fewer intact ribbon synapses. We show in zebrafish that, initially, Nrxn3 loss does not alter pre- and postsynapse numbers but, later, synapses fail to pair, leading to postsynapse loss. We also demonstrate that Nrxn3 subtly influences synapse selectivity in zebrafish lateral-line hair cells that detect anterior flow. Loss of Nrxn3 leads to a 60% loss of synapses in zebrafish, which dramatically reduces pre- and postsynaptic responses. Despite fewer synapses, auditory responses in zebrafish and mice are unaffected. This work demonstrates that Nrxn3 is a crucial and conserved molecule required for the maturation of ribbon synapses. Understanding how ribbon synapses mature is essential to generating new therapies to treat synaptopathies linked to auditory or vestibular dysfunction.

Active mechanical amplification of sound occurs in cochlear outer hair cells (OHCs) that change their length with oscillations of their membrane potential. Such length changes are the proposed cellular source of the cochlear amplifier, and prestin is the motor protein responsible for OHC electromotility. Previous findings have shown that mice lacking prestin displayed a loss of OHC electromotility, subsequent loss of distortion-product otoacoustic emissions, and a 40-60 dB increase in hearing thresholds. In this study we were interested in studying the functional consequences of the complete loss of cochlear amplification on neural coding of frequency selectivity, tuning, and temporal processing in the auditory midbrain. We recorded near-field auditory evoked potentials and multi-unit activity from the inferior colliculus (IC) of prestin (-/-) null and prestin (+/+) wild-type control mice and determined frequency response areas (FRAs), tuning sharpness, and gap detection to tone bursts and silent gaps embedded in broadband noise. We were interested in determining if the moderate to severe sensorineural hearing loss associated with the loss of motor protein prestin would also impair auditory midbrain temporal-processing measures, or if compensatory mechanisms within the brainstem could compensate for the loss of prestin. In prestin knockout mice we observed that there are severe impairments in midbrain tuning, thresholds, excitatory drive, and gap detection suggesting that brainstem and midbrain processing could not overcome the auditory processing deficits afforded by the loss of OHC electromotility mediated by the prestin protein.

Naked mole-rats are extremely social and extremely vocal rodents, displaying a wide range of functionally distinct call types and vocalizing almost continuously. Their vocalizations are low frequency, and a behavioral audiogram has shown that naked mole-rats, like other subterranean mammals, hear only low frequencies. Hence, the frequency range of their hearing and vocalizations appears to be well matched. However, even at low frequencies, naked mole-rats show very poor auditory thresholds, suggesting vocal communication may be effective only over short distances. However, in a tunnel environment where low frequency sounds propagate well and background noise is low, it may be that vocalizations travel considerable distances at suprathreshold intensities. Here, we confirmed hearing sensitivity using the auditory brainstem response; we characterized signature and alarm calls in intensity and frequency domains and we measured the effects of propagation through tubes with the diameter of naked mole-rat tunnels. Signature calls-used for intimate communication-could travel 3-8 m at suprathreshold intensities, and alarm calls (lower frequency and higher intensity), could travel up to 15 m. Despite this species' poor hearing sensitivity, the naked mole-rat displays a functional, coupled auditory-vocal communication system-a hallmark principle of acoustic communication systems across taxa.

Animal models have demonstrated that tinnitus is a pathology of dysfunctional excitability in the central auditory system, in particular in the dorsal cochlear nucleus (DCN) of the brainstem. We used a murine model and studied whether acoustic over-exposure leading to hearing loss and tinnitus, affects long-term potentiation (LTP) at DCN multisensory synapses. Whole cell and field potential recordings were used to study the effects on release probability and synaptic plasticity, respectively in brainstem slices. Shifts in hearing threshold were quantified by auditory brainstem recordings, and gap-induced prepulse inhibition of the acoustic startle reflex was used as an index for tinnitus. An increased release probability that saturated LTP and thereby induced metaplasticity at DCN multisensory synapses, was observed 4-5days following acoustic over-exposure. Perfusion of an NMDA receptor antagonist or decreasing extracellular calcium concentration, decreased the release probability and restored LTP following acoustic over-exposure. In vivo administration of magnesium-threonate following acoustic over-exposure restored LTP at DCN multisensory synapses, and reduced gap detection deficits observed four months following acoustic over-exposure. These observations suggest that consequences of noise-induced metaplasticity could underlie the gap detection deficits that follow acoustic over-exposure, and that early therapeutic intervention could target metaplasticity and alleviate tinnitus.

Large conductance, voltage‐ and Ca 2+ ‐activated K + (BK) channels in inner hair cells (IHCs) of the cochlea are essential for hearing. However, germ‐line deletion of BKα, the pore‐forming subunit KCNMA1 of the BK channel, surprisingly did not affect hearing thresholds in the first postnatal weeks, even though altered IHC membrane time constants, decreased IHC receptor potential alternating current/direct current ratio, and impaired spike timing of auditory fibers were reported in these mice. To investigate the role of IHC BK channels for central auditory processing, we generated a conditional mouse model with hair cell‐specific deletion of BKα from postnatal day 10 onward. This had an unexpected effect on temporal coding in the central auditory system: neuronal single and multiunit responses in the inferior colliculus showed higher excitability and greater precision of temporal coding that may be linked to the improved discrimination of temporally modulated sounds observed in behavioral training. The higher precision of temporal coding, however, was restricted to slower modulations of sound and reduced stimulus‐driven activity. This suggests a diminished dynamic range of stimulus coding that is expected to impair signal detection in noise. Thus, BK channels in IHCs are crucial for central coding of the temporal fine structure of sound and for detection of signals in a noisy environment.—Kurt, S., Sausbier, M., Rüttiger, L., Brandt, N., Moeller, C. K., Kindler, J., Sausbier, U., Zimmermann, U., van Straaten, H., Neuhuber, W., Engel, J., Knipper, M., Ruth, P., Schulze, H. Critical role for cochlear hair cell BK channels for coding the temporal structure and dynamic range of auditory information for central auditory processing. FASEB J. 26, 3834–3843 (2012). www.fasebj.org