Loss of neuronal activity facilitates surface accumulation of p75NTR and cell death in avian cochlear nucleus.

Sensorineural hearing loss causes cell death in central auditory neurons, but molecular mechanisms of triggering this process are not fully understood. We report here that loss of afferent activity promotes cell death by facilitating proBDNF-p75NTR signals in cochlear nucleus of chicks around hatch. RNA-seq analyses revealed up-regulation of genes related to proBDNF-p75NTR-JNK signals as well as apoptosis at the nucleus within 24hours after unilateral cochlea deprivation.

CDK5/p35-Dependent Microtubule Reorganization Contributes to Homeostatic Shortening of the Axon Initial Segment.

The structural plasticity of the axon initial segment (AIS) contributes to the homeostatic control of activity and optimizes the function of neural circuits; however, the underlying mechanisms are not fully understood. In this study, we prepared a slice culture containing nucleus magnocellularis from chickens of both sexes that reproduces most features of AIS plasticity , regarding its effects on characteristics of AIS and cell-type specificity, and revealed that microtubule reorganization via activation of CDK5 underlies plasticity. Treating the culture with a high-K medium shortened the AIS and reduced sodium current and membrane excitability, specifically in neurons tuned to high-frequency sound, creating a tonotopic difference in AIS length in the nucleus.

Cellular Strategies for Frequency-Dependent Computation of Interaural Time Difference.

Binaural coincidence detection is the initial step in encoding interaural time differences (ITDs) for sound-source localization. In birds, neurons in the nucleus laminaris (NL) play a central role in this process. These neurons receive excitatory synaptic inputs on dendrites from both sides of the cochlear nucleus and compare their coincidences at the soma.

Dendritic synapse geometry optimizes binaural computation in a sound localization circuit.

Clustering of synapses allows neurons to overcome attenuation of electrical signals at dendrites. However, we show in avian binaural coincidence detectors computing interaural time difference for sound localization that clustering of synapses rather promotes the dendritic attenuation but augments the intensity tolerance of the binaural computations. Using glutamate uncaging, we found in the neurons that synapses were clustered at distal dendritic branches.

Tonotopic Specializations in Number, Size, and Reversal Potential of GABAergic Inputs Fine-Tune Temporal Coding at Avian Cochlear Nucleus.

GABAergic inhibition in neurons plays a critical role in determining the output of neural circuits. Neurons in avian nucleus magnocellularis (NM) use several tonotopic-region-dependent specializations to relay the timing information of sound in the auditory nerve to higher auditory nuclei. Previously, we showed that feedforward GABAergic inhibition in NM has a different dependence on the level of auditory nerve activity, with the low-frequency region having a low-threshold and linear relationship, while the high-frequency region has a high-threshold and step-like relationship.

Structural and Functional Refinement of the Axon Initial Segment in Avian Cochlear Nucleus during Development.

The axon initial segment (AIS) is involved in action potential initiation. Structural and biophysical characteristics of the AIS differ among cell types and/or brain regions, but the underlying mechanisms remain elusive. Using immunofluorescence and electrophysiological methods, combined with super-resolution imaging, we show in the developing nucleus magnocellularis of the chicken in both sexes that the AIS is refined in a tonotopic region-dependent manner.

Excitatory-Inhibitory Synaptic Coupling in Avian Nucleus Magnocellularis.

The activity of neurons is determined by the balance between their excitatory and inhibitory synaptic inputs. Neurons in the avian nucleus magnocellularis (NM) integrate monosynaptic excitatory and polysynaptic inhibitory inputs from the auditory nerve, and transmit phase-locked output to higher auditory centers. The excitatory input is graded tonotopically, such that neurons tuned to higher frequency receive fewer, but larger, axon terminals.

Tonotopic Differentiation of Coupling between Ca and Kv1.1 Expression in Brainstem Auditory Circuit.

Tonotopic differentiations of ion channels ensure sound processing across frequencies. Afferent input plays a critical role in differentiations. We demonstrate here in organotypic culture of chicken cochlear nucleus that expression of Kv1.

Auditory Input Shapes Tonotopic Differentiation of Kv1.1 Expression in Avian Cochlear Nucleus during Late Development.

Tonotopic differentiation is fundamental for signal processing in the auditory system. However, when and how this differentiation arises remain elusive. We addressed this issue using electrophysiology and immunohistochemistry in nucleus magnocellularis of chickens of both sexes, which is known to differ in the expression of Kv1.

Tonotopic Variation of the T-Type Ca Current in Avian Auditory Coincidence Detector Neurons.

Neurons in avian nucleus laminaris (NL) are binaural coincidence detectors for sound localization and are characterized by striking structural variations in dendrites and axon initial segment (AIS) according to their acoustic tuning [characteristic frequency (CF)]. T-type Ca (CaT) channels regulate synaptic integration and firing behavior at these neuronal structures. However, whether or how CaT channels contribute to the signal processing in NL neurons is not known.

Structural and Functional Plasticity at the Axon Initial Segment.

The axon initial segment (AIS) is positioned between the axonal and somato-dendritic compartments and plays a pivotal role in triggering action potentials (APs) and determining neuronal output. It is now widely accepted that structural properties of the AIS, such as length and/or location relative to the soma, change in an activity-dependent manner. This structural plasticity of the AIS is known to be crucial for homeostatic control of neuronal excitability.

Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity.

Structural plasticity of the axon initial segment (AIS), the trigger zone of neurons, is a powerful means for regulating neuronal activity. Here, we show that AIS plasticity is not limited to structural changes; it also occurs as changes in ion-channel expression, which substantially augments the efficacy of regulation. In the avian cochlear nucleus, depriving afferent inputs by removing cochlea elongated the AIS, and simultaneously switched the dominant Kv channels at the AIS from Kv1.

Activity-dependent regulation of excitable axonal domains.

Rapid action potential propagation along myelinated axons requires voltage-gated Na(+) channel clustering at the axon initial segments (AISs) and nodes of Ranvier. The AIS is intrinsically defined by cytoskeletal proteins expressed in axons, whereas nodes of Ranvier are formed by interaction between neurons and myelinating glia. These axonal domains have long been considered stable structures, but recent studies revealed that they are plastic and contribute to fine adjustment of neuronal activities and circuit function.

[Regulation of neural circuit function in the axon initial segment].

The axon initial segment (AIS) is a highly specialized neuronal subregion that separates axonal and somatodendritic compartments. The AIS is enriched with voltage-gated Na+ channels, and plays a critical role in determining neuronal activity. Recently, our understanding of AIS has seen major advances.

Plasticity of the axonal trigger zone.

The axon initial segment (AIS) is a specialized axonal compartment that is involved in conversion of synaptic potentials into action potentials. Recent studies revealed that structural properties of the AIS, such as length and position relative to the soma, are differentiated in a cell-specific manner and shape signal processing of individual neurons. Moreover, these structural properties are not fixed but vary in response to prolonged changes of neuronal activity, which readjusts action potential threshold and compensates for the changes of activity, indicating that this structural plasticity of the AIS works as a homeostatic mechanism and contributes to maintain neuronal activity.

Activity-dependent and activity-independent development of the axon initial segment.

The axon initial segment (AIS) is the site of spike initiation in neurons. Previous studies revealed that spatial distribution of the AIS varies greatly among neurons to meet their specific needs. However, when and how this differentiation arises is unknown.

Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members.

Background: TMEM16A and 16B work as Cl(-) channel, whereas 16F works as phospholipid scramblase. The function of other TMEM16 members is unknown.

Results: Using TMEM16F(-/-) cells, TMEM16C, 16D, 16F, 16G, and 16J were shown to be lipid scramblases.

The cooperation of sustained and phasic inhibitions increases the contrast of ITD-tuning in low-frequency neurons of the chick nucleus laminaris.

Neurons in the nucleus laminaris (NL) of birds detect the coincidence of binaural excitatory inputs from the nucleus magnocellularis (NM) on both sides and process the interaural time differences (ITDs) for sound localization. Sustained inhibition from the superior olivary nucleus is known to control the gain of coincidence detection, which allows the sensitivity of NL neurons to ITD tolerate strong-intensity sound. Here, we found a phasic inhibition in chicken brain slices that follows the ipsilateral NM inputs after a short time delay, sharpens coincidence detection, and may enhance ITD sensitivity in low-frequency NL neurons.

Activation of metabotropic glutamate receptors improves the accuracy of coincidence detection by presynaptic mechanisms in the nucleus laminaris of the chick.

Interaural time difference (ITD) is a major cue for localizing a sound source and is processed in the nucleus laminaris (NL) in birds. Coincidence detection (CD) is a crucial step for processing ITD and critically depends on the size and time course of excitatory postsynaptic potentials (EPSPs). Here, we investigated a role of metabotropic glutamate receptors (mGluRs) in the regulation of EPSP amplitude and CD in the NL of chicks.

Structural tuning and plasticity of the axon initial segment in auditory neurons.

The axon initial segment (AIS) that separates axonal and somato-dendritic compartments is a highly specialised neuronal structure enriched with voltage-gated Na(+) channels and functions as the site of spike initiation in neurons. The AIS was once thought to be uniform and static in structure, but has been found to be organised in a manner specific to the function of individual neurons and to exhibit plasticity with changes in synaptic inputs. Such structural specialisations are found in the avian auditory system.

Short- and long-term plasticity at the axon initial segment.

The axon initial segment (AIS) is a highly specialized neuronal subregion that is the site of action potential initiation and the boundary between axonal and somatodendritic compartments. In recent years, our understanding of the molecular structure of the AIS, its maturation, and its multiple fundamental roles in neuronal function has seen major advances. We are beginning to appreciate that the AIS is dynamically regulated, both over short timescales via adaptations in ion channel function, and long timescales via activity-dependent structural reorganization.

Plasticity at the axon initial segment.

Experience dependent alterations in neural activity are mediated by diverse forms of plasticity, which are conventionally thought to occur at either synaptic terminals and/or postsynaptic membrane, such as dendrites and cell soma. However, our recent study has revealed that plasticity is not limited to synaptic sites, but it also takes place at the site where neural activity arises, the axon initial segment (AIS), which is a highly specialized region in the axon concentrated with voltage-gated Na+ channels. We observed in an avian brainstem auditory neuron that the AIS reorganized itself to elongate after deprivation of sensory inputs, which augmented the excitability of the neuron.

Presynaptic activity regulates Na(+) channel distribution at the axon initial segment.

Deprivation of afferent inputs in neural circuits leads to diverse plastic changes in both pre- and postsynaptic elements that restore neural activity. The axon initial segment (AIS) is the site at which neural signals arise, and should be the most efficient site to regulate neural activity. However, none of the plasticity currently known involves the AIS.

Roles of axonal sodium channels in precise auditory time coding at nucleus magnocellularis of the chick.

How the axonal distribution of Na(+) channels affects the precision of spike timing is not well understood. We addressed this question in auditory relay neurons of the avian nucleus magnocellularis. These neurons encode and convey information about the fine structure of sounds to which they are tuned by generating precisely timed action potentials in response to synaptic inputs.