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A fast transient outward current in layer II/III neurons of rat perirhinal cortex
No full textThe perirhinal cortex (PRC) is a supra-modal cortical area that collects and integrates information originating from uni- and multi-modal neocortical regions, transmits it to the hippocampus, and receives a feedback from the hippocampus itself. The elucidation of the mechanisms that underlie the specific excitable properties of the different PRC neuronal types appears as an important step toward the understanding of the integrative functions of PRC. In this study, we investigated the biophysical properties of the transient, I (A)-type K(+) current recorded in pyramidal neurons acutely dissociated from layers II/III of PRC of the rat (P8-P16). The current activated at about -50 mV and showed a fast monoexponential decay (tau(h) >> 14 ms at -30 to +10 mV). I (A) recovery from inactivation also had a monoexponential time course. No significant differences in the biophysical properties or current density of I (A) were found in pyramidal neurons from rats of different ages. Application of 4-AP (1-5 mM) reversibly and selectively blocked I (A), and in current clamp conditions it increased spike duration and shortened the delay of the first spike during repetitive firing evoked by sustained depolarizing current injection. These properties are similar to those of the I (A) found in thalamic neurons and other cortical pyramidal neurons. Our results suggest that I (A) contributes to spike repolarization and to regulate both spike onset timing and firing frequency in PRC neurons
Functional interactions within the parahippocampal region revealed by voltage-sensitive dye imaging in the isolated guinea pig brain
Full text linkThe massive transfer of information from the neocortex to the entorhinal cortex (and vice versa) is hindered by a powerful inhibitory control generated in the perirhinal cortex. In vivo and in vitro experiments performed in rodents and cats support this conclusion, further extended in the present study to the analysis of the interaction between the entorhinal cortex and other parahippocampal areas, such as the postrhinal and the retrosplenial cortices. The experiments were performed in the in vitro isolated guinea pig brain by a combined approach based on electrophysiological recordings and fast imaging of optical signals generated by voltage-sensitive dyes applied to the entire brain by arterial perfusion. Local stimuli delivered in different portions of the perirhinal, postrhinal, and retrosplenial cortex evoked local responses that did not propagate to the entorhinal cortex. Neither high- and low-frequency-patterned stimulation nor paired associative stimuli facilitated the propagation of activity to the entorhinal region. Similar stimulations performed during cholinergic neuromodulation with carbachol were also ineffective in overcoming the inhibitory network that controls propagation to the entorhinal cortex. The pharmacological inactivation of GABAergic transmission by local application of bicuculline (1 mM) in area 36 of the perirhinal cortex facilitated the longitudinal (rostrocaudal) propagation of activity into the perirhinal/postrhinal cortices but did not cause propagation into the entorhinal cortex. Bicuculline injection in both area 35 and medial entorhinal cortex released the inhibitory control and allowed the propagation of the neural activity to the entorhinal cortex. These results demonstrate that, as for the perirhinal-entorhinal reciprocal interactions, also the connections between the postrhinal/retrosplenial cortices and the entorhinal region are subject to a powerful inhibitory control
IK,L properties of vestibular Type I hair cells are affected by the nerve calyx ending
Full text linkMammalian vestibular epithelia have a distinctive sensory cell , called Type I hair cell, that is contacted by an afferent calyx enveloping the entire cell basolateral membrane. Type I cells express a signature low-voltage-activated outward rectifying K+ current, IK,L, which is responsible for their low input resistance at rest . Despite its functional importance, however, IK,L biophysical properties and molecular profile have not yet been defined. Its voltage- and time-dependent properties have been reported to vary at different developmental stages, among cells at a same age, and also over time in the same cell. By using patch-clamp recording from in situ and dissociated mouse crista Type I cells, we found that the observed variability in IK,L properties may be accounted for by different degrees of K+ accumulation in the narrow space of the synaptic cleft between the hair cell and the residual nerve calyx. After complete calyx removal, IK,L properties in adult animals were in fact consistent among cells and did not change during the recording. IK,L in these cells showed a quite slow deactivation kinetics (time constant ~ 1 s at –80 mV), a complex activation kinetics best described by a three exponential function, a half-activation voltage of –69 mV, and a steep voltage dependence (S = 3.68). This study provides the first complete biophysical description of the genuine properties of IK,L, and suggests that in vivo IK,L properties are dependent on K+ accumulation into the synaptic cleft. Intercellular K+ accumulation might represent a direct way to change both the hair cell and the calyx membrane potential, thus allowing an additional form of communication that cooperates with the conventional glutamatergic synaptic transmission
Eps8 regulates K+ current expression in mouse cochlear inner but not outer hair cells nor in vestibular type I and type II hair cells
No full textEps8 is involved in modulating cell signaling and receptor trafficking, via its range of protein interactions. We recently showed that cochlear inner and outer hair cells of
Eps8 knockout (KO) mice, which are born deaf, show shorter stereocilia than wild type (WT) mice [1]. Inner, but not outer, hair cells, moreover, showed an altered expression of the mature array of voltage-dependent K+ channels, despite the fact that they express similar conductances. Vestibular hair cells of Eps8 KO mice show shorter stereocilia than normal [2], too. However, it is not known if this is accompanied by some functional defect. We therefore patch-clamp whole-cell recorded the voltage-dependent K+ currents from vestibular Type I and Type II hair cells of Eps8 KO and
WT mice at different postnatal developmental stages. We found that both vestibular hair cell types from KO mice showed a normal pattern of expression of K+ currents along with maturation up to the adult age. These results indicate that Eps8 is a specific regulator of K+ channel expression in mammalian cochlear inner hair cells. This notion appears particularly important in view of the recent discovery that a nonsense mutation in EPS8 is responsible for a non-syndromic form of human deafness [3]
Precision medicine: a new era for inner ear diseases
No full text: The inner ear is the organ responsible for hearing and balance. Inner ear dysfunction can be the result of infection, trauma, ototoxic drugs, genetic mutation or predisposition. Often, like for Ménière disease, the cause is unknown. Due to the complex access to the inner ear as a fluid-filled cavity within the temporal bone of the skull, effective diagnosis of inner ear pathologies and targeted drug delivery pose significant challenges. Samples of inner ear fluids can only be collected during surgery because the available procedures damage the tiny and fragile structures of the inner ear. Concerning drug administration, the final dose, kinetics, and targets cannot be controlled. Overcoming these limitations is crucial for successful inner ear precision medicine. Recently, notable advancements in microneedle technologies offer the potential for safe sampling of inner ear fluids and local treatment. Ultrasharp microneedles can reach the inner ear fluids with minimal damage to the organ, collect μl amounts of perilymph, and deliver therapeutic agents in loco. This review highlights the potential of ultrasharp microneedles, combined with nano vectors and gene therapy, to effectively treat inner ear diseases of different etiology on an individual basis. Though further research is necessary to translate these innovative approaches into clinical practice, these technologies may represent a true breakthrough in the clinical approach to inner ear diseases, ushering in a new era of personalized medicine
Authentic biophysical properties of IK,L in mammalian vestibular type I hair cells revealed after calyx removal
No full textMammalian vestibular epithelia are characterized by the expression of two different sensory cells named Type I and Type II hair cells. Different from Type II cells, the basolateral membrane of Type I cells shows two distinguishing properties: it is entirely wrapped by a single nerve terminal, called the calyx, and it expresses a low-voltage-activated outward rectifying K+ current, IK,L which is responsible for the much lower input
resistance at rest as compared to Type II hair cells. Strikingly, the principal biophysical features of IK,L have not been unequivocally described so far. In fact, its voltage- and time-dependent properties have been reported to vary widely not only among Type I hair cells, but also in the same cell over time. On the basis of our electrophysiological recordings from in situ and dissociated mouse crista Type I cells, we showed that the large variability in IK,L properties is attributable to different degrees of K+ accumulation in the narrow space of the synaptic cleft between the hair cell and the residual calyx. Hence, in order to obtain a genuine description of IK,L, we developed a procedure to refine the removal of the calyx prior to patching. Only once the calyx had been effectively removed could we show that the biophysical properties of IK,L are in fact consistent among cells, and quite constant during the recordings. In particular, IK,L
showed significantly slower deactivation kinetics (time constant: ~1s at –80 mV), a less negative voltage activation (half-activation voltage: -69 mV) and a steeper voltage dependence (S: 3.72mV) than previously reported. In conclusion, our data provide for the first time a complete description of the authentic biophysical properties of IK,L. As a corollary, we demonstrate that the calyx represents a strong barrier to K+ diffusion out of the synaptic cleft, which provides a direct way to depolarize either the hair cells and their calyx
Signal transmission in mature mammalian vestibular hair cells
Full text linkThe maintenance of balance and gaze relies on the faithful and rapid signaling of head movements to the brain. In mammals, vestibular organs contain two types of sensory hair cells, type-I and type-II, which convert the head motion-induced movement of their hair bundles into a graded receptor potential that drives action potential activity in their afferent fibers. While signal transmission in both hair cell types involves Ca2+-dependent quantal release of glutamate at ribbon synapses, type-I cells appear to also exhibit a non-quantal mechanism that is believed to increase transmission speed. However, the reliance of mature type-I hair cells on non-quantal transmission remains unknown. Here we investigated synaptic transmission in mammalian utricular hair cells using patch-clamp recording of Ca2+ currents and changes in membrane capacitance (ΔCm). We found that mature type-II hair cells showed robust exocytosis with a high-order dependence on Ca2+ entry. By contrast, exocytosis was approximately 10 times smaller in type-I hair cells. Synaptic vesicle exocytosis was largely absent in mature vestibular hair cells of CaV1.3 (CaV1.3−/−) and otoferlin (Otof−/−) knockout mice. Even though Ca2+-dependent exocytosis was small in type-I hair cells of wild-type mice, or absent in CaV1.3−/− and Otof−/−mice, these cells were able to drive action potential activity in the postsynaptic calyces. This supports a functional role for non-quantal synaptic transmission in type-I cells. The large vesicle pools in type-II cells would facilitate sustained transmission of tonic or low-frequency signals. In type-I cells, the restricted vesicle pool size, together with a rapid non-quantal mechanism, could allow them to sustain high-frequency phasic signal transmission at their specialized large calyceal synapses
The biophysical properties of IK,L in mammalian vestibular type I hair cells and how they are affected by the nerve calyx
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