Focusing on the Emerging Role of Kainate Receptors in the Dorsal Cochlear Nucleus (DCN) and Cerebellum.

Mammals have a dorsal cochlear nucleus (DCN), which is thought to be a cerebellum-like structure with similar features in terms of structure and microcircuitry to the cerebellum. Both the DCN and cerebellum perform their functions depending on synaptic and neuronal networks mediated by various glutamate receptors. Kainate receptors (KARs) are one class of the glutamate receptor family and are strongly expressed in the hippocampus, the cerebellum, and cerebellum-like structures. The cellular distribution and the potential role of KARs in the hippocampus have been extensively investigated. However, the cellular distribution and the potential role of KARs in cerebellum-like structures, including the DCN and cerebellum, are poorly understood. In this review, we summarize the similarity between the DCN and cerebellum at the levels of structure, circuitry, and cell type as well as the investigations referring to the expression patterns of KARs in the DCN and cerebellum according to previous studies. Recent studies on the role of KARs have shown that KARs mediate a bidirectional modulatory effect at parallel fiber (PF)-Purkinje cell (PC) synapses in the cerebellum, implying insights into their roles in cerebellum-like structures, including the DCN, that remain to be explored in the coming years.

Electrically evoked auditory brainstem responses in deaf patients with Mondini malformation during cochlear implantation.

PURPOSE: To investigate the auditory pathway functions in deaf patients with Mondini malformation using the electrically evoked auditory brainstem response (EABR) during cochlear implantation (CI). METHODS: A total of 58 patients with severe to profound sensorineural hearing loss (SNHL) were included in this study. Of these patients, 27 cases had Mondini malformation and 31 control cases had no inner ear malformations (IEMs). Intraoperative EABRs evoked by electrical stimulation at the round window niche (RWN) and round window membrane (RWM) were recorded. RESULTS: Patients with Mondini malformation showed significantly lower EABR extraction rates than those with no IEMs did. However, for patients who showed EABRs, no significant difference in EABR thresholds, wave III (eIII) latencies, wave V (eV) latencies or eIII-eV latency intervals was found between two groups. CONCLUSION: The physiological functions of the peripheral auditory system in patients with Mondini malformation may divide into opposite extremes, as revealed by a robust EABR and the absence of the EABR, respectively. The auditory conduction function should be objectively and individually evaluated for patients with Mondini malformation by the EABR.

Sodium salicylate enhances neural excitation via reducing GABAergic transmission in the dentate gyrus area of rat hippocampus in vivo.

Sodium salicylate, one of the non-steroidal anti-inflammatory drugs, is widely prescribed in the clinic, but a high dose of usage can cause hyperactivity in the central nervous system, including the hippocampus. At present, the neural mechanism underlying the induced hyperactivity is not fully understood, in particular, in the hippocampus under an in vivo condition. In this study, we found that systemic administration of sodium salicylate increased the field excitatory postsynaptic potential slope and the population spike amplitude in a dose-dependent manner in the hippocampal dentate gyrus area of rats with in vivo field potential extracellular recordings, which indicates that sodium salicylate enhances basal synaptic transmission and neural excitation. In the presence of picrotoxin, a GABA-A receptor antagonist, sodium salicylate failed to increase the initial slope of the field excitatory postsynaptic potential and the amplitude of the population spike in vivo. To further explore how sodium salicylate enhances the neural excitation, we made whole-cell patch-clamp recordings from hippocampal slices. We found that perfusion of the slice with sodium salicylate decreased electrically evoked GABA receptor-mediated currents, increased paired-pulse ratio, and lowered frequency and amplitude of miniature inhibitory postsynaptic currents. Together, these results demonstrate that sodium salicylate enhances the neural excitation through suppressing GABAergic synaptic transmission in presynaptic and postsynaptic mechanisms in the hippocampal dentate gyrus area. Our findings may help understand the side effects caused by sodium salicylate in the central nervous system.

Serotonergic regulation of excitability of principal cells of the dorsal cochlear nucleus.

The dorsal cochlear nucleus (DCN) is one of the first stations within the central auditory pathway where the basic computations underlying sound localization are initiated and heightened activity in the DCN may underlie central tinnitus. The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT), is associated with many distinct behavioral or cognitive states, and serotonergic fibers are concentrated in the DCN. However, it remains unclear what is the function of this dense input. Using a combination of in vitro electrophysiology and optogenetics in mouse brain slices, we found that 5-HT directly enhances the excitability of fusiform principal cells via activation of two distinct 5-HT receptor subfamilies, 5-HT2A/2CR (5-HT2A/2C receptor) and 5-HT7R (5-HT7 receptor). This excitatory effect results from an augmentation of hyperpolarization-activated cyclic nucleotide-gated channels (Ih or HCN channels). The serotonergic regulation of excitability is G-protein-dependent and involves cAMP and Src kinase signaling pathways. Moreover, optogenetic activation of serotonergic axon terminals increased excitability of fusiform cells. Our findings reveal that 5-HT exerts a potent influence on fusiform cells by altering their intrinsic properties, which may enhance the sensitivity of the DCN to sensory input.

Activation of synaptic group II metabotropic glutamate receptors induces long-term depression at GABAergic synapses in CNS neurons.

Metabotropic glutamate receptor (mGluR)-dependent homosynaptic long-term depression (LTD) has been studied extensively at glutamatergic synapses in the CNS. However, much less is known about heterosynaptic long-term plasticity induced by mGluRs at inhibitory synapses. Here we report that pharmacological or synaptic activation of group II mGluRs (mGluR II) induces LTD at GABAergic synapses without affecting the excitatory glutamatergic transmission in neurons of the chicken cochlear nucleus. Coefficient of variation and failure rate analysis suggested that the LTD was expressed presynaptically. The LTD requires presynaptic spike activity, but does not require the activation of NMDA receptors. The classic cAMP-dependent protein kinase A signaling is involved in the transduction pathway. Remarkably, blocking mGluR II increased spontaneous GABA release, indicating the presence of tonic activation of mGluR II by ambient glutamate. Furthermore, synaptically released glutamate induced by electrical stimulations that concurrently activated both the glutamatergic and GABAergic pathways resulted in significant and constant suppression of GABA release at various stimulus frequencies (3.3, 100, and 300 Hz). Strikingly, low-frequency stimulation (1 Hz, 15 min) of the glutamatergic synapses induced heterosynaptic LTD of GABAergic transmission, and the LTD was blocked by mGluR II antagonist, indicating that synaptic activation of mGluR II induced the LTD. This novel form of long-term plasticity in the avian auditory brainstem may play a role in the development as well as in temporal processing in the sound localization circuit.

Danshensu reduces neuronal excitability by enhancing potassium currents in bushy cells in the mouse cochlear nucleus.

Danshensu, also known as salvianic acid A, is a primary active compound extracted from a traditional Chinese herb Danshen (Salvia miltiorrhiza). While its antioxidative and neuroprotective effects are well-documented, the underlying mechanisms are poorly understood. In this study, we sought out to investigate if and how Danshensu modulates neuronal excitability and voltage-gated ionic currents in the central nervous system. We prepared brain slices of the mouse brainstem and performed patch-clamp recording in bushy cells in the anteroventral cochlear nucleus, with or without Danshensu incubation for 1 h. QX-314 was used internally to block Na+ current, while tetraethylammonium and 4-aminopyridine were used to isolate different subtypes of K+ current. We found that Danshensu of 100 µm decreased the input resistance of bushy cells by approximately 60% and shifted the voltage threshold of spiking positively by approximately 7 mV, resulting in significantly reduced excitability. Furthermore, we found this reduced excitability by Danshensu was caused by enhanced voltage-gated K+ currents in these neurons, including both low voltage-activated IK,A, by approximately 100%, and high voltage-activated IK,dr, by approximately 30%. Lastly, we found that the effect of Danshensu on K+ currents was dose-dependent in that no enhancement was found for Danshensu of 50 µm and Danshensu of 200 µm failed to cause significantly more enhancement on K+ currents when compared to that of 100 µm. We found that Danshensu reduced neuronal excitability in the central nervous system by enhancing voltage-gated K+ currents, providing mechanistic support for its neuroprotective effect widely seen in vivo.

Resveratrol prevents hearing loss and a subregion specific- reduction of serotonin reuptake transporter induced by noise exposure in the central auditory system.

Prolonged or excessive exposure to noise can lead to hearing loss, tinnitus and hypersensitivity to sound. The effects of noise exposure on main excitatory and inhibitory neurotransmitter systems in auditory pathway have been extensively investigated. However, little is known about aberrant changes in neuromodulator systems caused by noise exposure. In the current study, we exposed 2-month-old mice to a narrow band noise at 116 dB SPL for 6 h or sham exposure, assessed auditory brainstem responses as well as examined the expression of serotonin reuptake transporter (SERT) in the cochlear nucleus (CN), inferior colliculus (IC), and primary auditory cortex (Au1) using immunohistochemistry. We found that noise exposure resulted in a significant increase in hearing thresholds at 4, 8, 16, 24, and 32 kHz, as well as led to a significant reduction of SERT in dorsal cochlear nucleus (DCN), dorsal IC (ICd), external IC (ICe), and Au1 layers I-IV. This reduction of SERT in these subregions of central auditory system was partially recovered 15 or 30 days after noise exposure. Furthermore, we examined efficacy of resveratrol (RSV) on hearing loss and loss of SERT induced by noise exposure. The results demonstrated that RSV treatment significantly attenuated threshold shifts of auditory brainstem responses and loss of SERT in DCN, ICd, ICe, and Au1 layers I-IV. These findings show that noise exposure can cause hearing loss and subregion-specific loss of SERT in the central auditory system, and RSV treatment could attenuate noise exposure-induced hearing loss and loss of SERT in central auditory system.

Electrically Evoked Auditory Brainstem Responses in Children Fitted with Hearing Aids Prior to Cochlear Implantation.

This study investigates the effect of hearing aid use on the peripheral auditory pathways in children with sensorineural hearing loss prior to cochlear implantation, as revealed by the electrically evoked auditory brainstem response (EABR). Forty children with hearing aids were recruited. Half of them had normal inner ear structures and the other half had inner ear malformations (IEMs). The EABR was evoked by electrically stimulating the round window niche (RWN) and round window membrane (RWM) during the cochlear implantation operation. The onset age of hearing aid use was significantly correlated with the peak latencies, but not amplitudes, of the wave III (eIII) and wave V (eV). Higher EABR thresholds were found for RWN stimulation than for RWM stimulation and in the children with IEMs than in those without IEMs. Our study provides neurophysiological evidence that earlier use of hearing aids may ameliorate physiological functions of the peripheral auditory pathway in children with and without IEMs. The EABR evoked by the electrical stimulation at RWM is more sensitive compared with that at RWN for evaluating functions of the auditory conduction pathway.

Ambient GABA-activated tonic inhibition sharpens auditory coincidence detection via a depolarizing shunting mechanism.

Tonic inhibition mediated by extrasynaptic GABA(A) receptors (GABA(A)Rs) has emerged as a novel form of neural inhibition in the CNS. However, little is known about its presence and function in the auditory system. Using whole-cell recordings in brain slices, we identified a tonic current mediated by GABA(A)Rs containing the δ subunit in middle/high-characteristic-frequency neurons of the chicken nucleus laminaris, the first interaural time difference encoder that computes information for sound localization. This tonic conductance was activated by ambient concentrations of GABA released from synaptic vesicles. Furthermore, pharmacological manipulations of the conductance demonstrated its essential role in coincidence detection. Remarkably, this depolarizing tonic conductance was strongly inhibitory primarily because of its shunting effect. These results demonstrate a novel role for tonic inhibition in central auditory information processing.

Two GABAA responses with distinct kinetics in a sound localization circuit.

The temporal characteristics and functional diversity of GABAergic inhibition are determined by the spatiotemporal neurotransmitter profile, intrinsic properties of GABAA receptors, and other factors. Here, we report two distinct GABAA responses and the underlying mechanisms in neurons of the chicken nucleus laminaris (NL), the first encoder of interaural time difference for sound localization in birds. The time course of the postsynaptic GABAA currents in NL neurons, recorded with whole-cell voltage clamp, differed between different characteristic frequency (CF) regions. Compared to low-CF (LF) neurons, middle/high-CF (MF/HF) neurons had significantly slower IPSCs, with a 2.6-fold difference in the decay time constants of spontaneous IPSCs and a 5.3-fold difference in the decay of IPSCs elicited by single-pulse stimulus. Such differences were especially dramatic when IPSCs were elicited by train stimulations at physiologically relevant frequencies, and at high stimulus intensities. To account for these distinct GABAA responses, we showed that MF/HF neurons exhibited more prominent asynchronous release of GABA. Supporting this observation, replacement of extracellular Ca2+ with Sr2+ increased the decay of IPSCs in LF neurons, and EGTA-AM reduced the decay of IPSCs in MF/HF neurons. Furthermore, pharmacological evidence suggests that GABA spillover plays a greater role in prolonging the IPSCs of MF/HF neurons. Consequently, under whole-cell current clamp, synaptically released GABA produced short- and long-lasting suppression of the neuronal excitability of LF and MF/HF neurons, respectively. Taken together, these results suggest that the GABAergic inputs to NL neurons may exert a dynamic modulation of interaural time difference (ITD) coding in a CF-dependent manner.

Resveratrol noncompetitively inhibits glycine receptor-mediated currents in neurons of rat central auditory neurons.

Resveratrol, a naturally occurring stilbene found in red wine, is known to modulate the activity of several types of ion channels and membrane receptors, including Ca2+, K+, and Na+ ion channels. However, little is known about the effects of resveratrol on some important receptors, such as glycine receptors and GABAA receptors, in the central nervous system (CNS). In the present study, the effects of resveratrol on glycine receptor or GABAA receptor-mediated currents in cultured rat inferior colliculus (IC) and auditory cortex (AC) neurons were studied using whole-cell voltage-clamp recordings. Resveratrol itself did not evoke any currents in IC neurons but it reversibly decreased the amplitude of glycine-induced current (IGly) in a concentration-dependent manner. Resveratrol did not change the reversal potential of IGly but it shifted the concentration-response relationship to the right without changing the Hill coefficient and with decreasing the maximum response of IGly. Interestingly, resveratrol inhibited the amplitude of IGly but not that of GABA-induced current (IGABA) in AC neurons. More importantly, resveratrol inhibited GlyR-mediated but not GABAAR-mediated inhibitory postsynaptic currents in IC neurons using brain slice recordings. Together, these results demonstrate that resveratrol noncompetitively inhibits IGly in auditory neurons by decreasing the affinity of glycine to its receptor. These findings suggest that the native glycine receptors but not GABAA receptors in central neurons are targets of resveratrol during clinical administrations.

Cross-talk pattern between GABAA- and glycine-receptors in CNS neurons is shaped by their relative expression levels.

GABAA receptors (GABAARs) and glycine receptors (GlyRs) are two principal inhibitory chloride ion channels in the central nervous system. The two receptors do not function independently but cross-talk to each other, i.e., the activation of one receptor would inhibit the other. This cross-talk is present in different patterns across various regions in the central nervous system; however, the factor that determines these patterns is not understood. Here, we show that the pattern of cross-talk between the two receptors is shaped by their relative expression level in a neuron: a higher expression level correlates with louder talk. In line with a tendency of decrease in expression level of GlyRs and increase in expression level of GABAARs from the spinal cord, the brainstem to the neocortex, GlyRs talked much louder (i.e. produced greater inhibition) than GABAARs (one-way pattern) in spinal cord neurons, about equally loud as GABAARs (symmetric pattern) in inferior colliculus neurons and less loud (i.e. less inhibition) than GABAARs (asymmetric pattern) in auditory cortex neurons. Overexpression of GlyRs in inferior colliculus neurons produced an asymmetric pattern that should otherwise have been observed in spinal cord neurons. These expression level-dependent patterns of cross-talk between the two receptors may suggest how the central nervous system uses an alternative mechanism to maintain a delicate level of inhibition through adjusting the proportion of the two receptors in a neuron along its pathway.

A Central Amygdala Input to the Parafascicular Nucleus Controls Comorbid Pain in Depression.

While comorbid pain in depression (CP) occurs at a high rate worldwide, the neural connections underlying the core symptoms of CP have yet to be elucidated. Here, we define a pathway whereby GABAergic neurons from the central nucleus of the amygdala (GABACeA) project to glutamatergic neurons in the parafascicular nucleus (GluPF). These GluPF neurons relay directly to neurons in the second somatosensory cortex (S2), a well-known area involved in pain signal processing. Enhanced inhibition of the GABACeA→GluPF→S2 pathway is found in mice exhibiting CP symptoms. Reversing this pathway using chemogenetic or optogenetic approaches alleviates CP symptoms. Together, the current study demonstrates the putative importance of the GABACeA→GluPF→S2 pathway in controlling at least some aspects of CP.

Developmental stability of taurine's activation on glycine receptors in cultured neurons of rat auditory cortex.

Taurine is an endogenous amino acid that can activate glycine and/or gamma-aminobutyric acid type A (GABA(A)) receptors in the central nervous system. During natural development, taurine's receptor target undergoes a shift from glycine receptors to GABA(A) receptors in cortical neurons. Here, we demonstrate that taurine's receptor target in cortical neurons remains stable during in vitro development. With whole-cell patch-clamp recordings, we found that taurine always activated glycine receptors, rather than GABA(A) receptors, in neurons of rat auditory cortex cultured for 5-22 days. Our results suggest that the functional sensitivity of glycine and GABA(A) receptors to taurine is critically regulated by their developmental environments.

Anatomy and Physiology of Metabotropic Glutamate Receptors in Mammalian and Avian Auditory System.

Glutamate, as the major excitatory neurotransmitter used in the vertebrate brain, activates ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs), which mediate fast and slow neuronal actions, respectively. mGluRs play important modulatory roles in many brain areas, forming potential targets for drugs developed to treat brain disorders. Here, we review studies on mGluRs in the mammalian and avian auditory system. Although anatomical expression of mGluRs in the cochlear nucleus has been well characterized, data for other auditory nuclei await more systematic investigations especially at the electron microscopy level. The physiology of mGluRs has been extensively studied using in vitro brain slice preparations, with a focus on the auditory circuitry in the brainstem. These in vitro physiological studies have demonstrated that mGluRs participate in synaptic transmission, regulate ionic homeostasis, induce synaptic plasticity, and maintain the balance between Excitation and Inhibition (E/I) in a variety of auditory structures. However, the modulatory roles of mGluRs in auditory processing remain largely unclear at the system and behavioral levels, and the functions of mGluRs in auditory disorders remain entirely unknown.

Serotonergic Modulation of Sensory Representation in a Central Multisensory Circuit Is Pathway Specific.

Many studies have explored how neuromodulators affect synaptic function, yet little is known about how they modify computations at the microcircuit level. In the dorsal cochlear nucleus (DCN), a region that integrates auditory and multisensory inputs from two distinct pathways, serotonin (5-HT) enhances excitability of principal cells, predicting a generalized reduction in sensory thresholds. Surprisingly, we found that when looked at from the circuit level, 5-HT enhances signaling only from the multisensory input, while decreasing input from auditory fibers. This effect is only partially explained by an action on auditory nerve terminals. Rather, 5-HT biases processing for one input pathway by simultaneously enhancing excitability in the principal cell and in a pathway-specific feed-forward inhibitory interneuron. Thus, by acting on multiple targets, 5-HT orchestrates a fundamental shift in representation of convergent auditory and multisensory pathways, enhancing the potency of non-auditory signals in a classical auditory pathway.

Morphometry of otoliths in chicken macula lagena.

The macula lagena located at the apical end of the cochlea in birds is characterized by the presence of numerous otoliths with unclear sensory functions. These otoliths are reported to be similar to those in the vestibular system but their detailed features in morphology are unknown. In the present study, we examined the number, size and shape of otoliths from the macula lagena in Chinese domestic chickens (Gallus Ling Nan) with a scanning electron microscope for morphometry. For chickens aged 10-15 post-hatch days, the otoliths in each macula lagena were counted to be 16,055 +/- 4038 (mean +/- S.D., n = 4). The average length and width were 12.98 +/- 3.70 microm and 5.10 +/- 1.48 microm (n = 526 otoliths), respectively. The ratio of length to width for the otolith was 2.58 +/- 0.39 (n = 526 otoliths) and remained relatively constant despite their variations in physical size. Almost all the otoliths were in regular shape and appeared like isolated cylinders with smooth facets at each end, but a few of them (0.025% of 64,221 otoliths screened) were found to be in odd shapes, such as T-shape and cross-shape. The results suggest that otoliths in the macula lagena and those in the vestibular system of bird's inner ear have similar physical properties and may play a similar role in sensing gravitational and acceleration signals.

Taurine acts as a glycine receptor agonist in slices of rat inferior colliculus.

Taurine is an important endogenous amino acid for neural development and for many physiological functions, but little is known about its functional role in the central auditory system. We investigated in young rats (P10-P14) the effects of taurine on the neuronal responses and synaptic transmissions in the central nucleus of the inferior colliculus (ICC) with a brain slice preparation and with whole-cell patch-clamp recordings. Perfusion of taurine at 1mM reliably evoked a current across the membrane and decreased the input resistance in neurons of the ICC. Taurine also depressed the spontaneous and current-evoked firing of ICC neurons. All these effects were reversible after washout and could be blocked by 3 microM strychnine, an antagonist of glycine receptors, but not by 10 microM bicuculline, an antagonist of GABA(A) receptors. When the inhibitory receptors were not pharmacologically blocked, taurine reversibly reduced the postsynaptic currents/potentials evoked by electrically stimulating the commissure of the inferior colliculus or the ipsilateral lateral lemniscus. The results demonstrate that taurine reduces the neuronal excitability and depresses the synaptic transmission in the ICC by activating glycine-gated chloride channels. Our findings suggest that taurine acts as a ligand of glycine receptors in the ICC and can be involved in the information processing of the central auditory system similarly like the neurotransmitter glycine.

Interplay between low threshold voltage-gated K(+) channels and synaptic inhibition in neurons of the chicken nucleus laminaris along its frequency axis.

Central auditory neurons that localize sound in horizontal space have specialized intrinsic and synaptic cellular mechanisms to tightly control the threshold and timing for action potential generation. However, the critical interplay between intrinsic voltage-gated conductances and extrinsic synaptic conductances in determining neuronal output are not well understood. In chicken, neurons in the nucleus laminaris (NL) encode sound location using interaural time difference (ITD) as a cue. Along the tonotopic axis of NL, there exist robust differences among low, middle, and high frequency (LF, MF, and HF, respectively) neurons in a variety of neuronal properties such as low threshold voltage-gated K(+) (LTK) channels and depolarizing inhibition. This establishes NL as an ideal model to examine the interactions between LTK currents and synaptic inhibition across the tonotopic axis. Using whole-cell patch clamp recordings prepared from chicken embryos (E17-E18), we found that LTK currents were larger in MF and HF neurons than in LF neurons. Kinetic analysis revealed that LTK currents in MF neurons activated at lower voltages than in LF and HF neurons, whereas the inactivation of the currents was similar across the tonotopic axis. Surprisingly, blockade of LTK currents using dendrotoxin-I (DTX) tended to broaden the duration and increase the amplitude of the depolarizing inhibitory postsynaptic potentials (IPSPs) in NL neurons without dependence on coding frequency regions. Analyses of the effects of DTX on inhibitory postsynaptic currents led us to interpret this unexpected observation as a result of primarily postsynaptic effects of LTK currents on MF and HF neurons, and combined presynaptic and postsynaptic effects in LF neurons. Furthermore, DTX transferred subthreshold IPSPs to spikes. Taken together, the results suggest a critical role for LTK currents in regulating inhibitory synaptic strength in ITD-coding neurons at various frequencies.