Synapse Counts Research Articles

Age-Related Deficits in Binaural Hearing: Contribution of Peripheral and Central Effects.

Pure-tone audiograms often poorly predict elderly humans' ability to communicate in everyday complex acoustic scenes. Binaural processing is crucial for discriminating sound sources in such complex acoustic scenes. The compromised perception of communication signals presented above hearing threshold has been linked to both peripheral and central age-related changes in the auditory system. Investigating young and old Mongolian gerbils of both sexes, an established model for human hearing, we demonstrate age-related supra-threshold deficits in binaural hearing using behavioral, electrophysiological, anatomical, and imaging methods. Binaural processing ability was measured as the binaural masking level difference (BMLD), an established measure in human psychophysics. We tested gerbils behaviorally with "virtual headphones," recorded single-unit responses in the auditory midbrain and evaluated gross midbrain and cortical responses using positron emission tomography (PET) imaging. Furthermore, we obtained additional measures of auditory function based on auditory brainstem responses, auditory-nerve synapse counts, and evidence for central inhibitory processing revealed by PET. BMLD deteriorates already in middle-aged animals having normal audiometric thresholds and is even worse in old animals with hearing loss. The magnitude of auditory brainstem response measures related to auditory-nerve function and binaural processing in the auditory brainstem also deteriorate. Furthermore, central GABAergic inhibition is affected by age. Because the number of synapses in the apical turn of the inner ear was not reduced in middle-aged animals, we conclude that peripheral synaptopathy contributes little to binaural processing deficits. Exploratory analyses suggest increased hearing thresholds, altered binaural processing in the brainstem and changed central GABAergic inhibition as potential contributors.

Impact of miR-29c-3p in the Nucleus Accumbens on Methamphetamine-Induced Behavioral Sensitization and Neuroplasticity-Related Proteins.

Methamphetamine (METH) abuse inflicts both physical and psychological harm. While our previous research has established the regulatory role of miR-29c-3p in behavior sensitization, the underlying mechanisms and target genes remain incompletely understood. In this study, we employed the isobaric tags for relative and absolute quantitation (iTRAQ) technique in conjunction with Ingenuity pathway analysis (IPA) to probe the putative molecular mechanisms of METH sensitization through miR-29c-3p inhibition. Through a microinjection of AAV-anti-miR-29c-3p into the nucleus accumbens (NAc) of mice, we observed the attenuation of METH-induced locomotor effects. Subsequent iTRAQ analysis identified 70 differentially expressed proteins (DEPs), with 22 up-regulated potential target proteins identified through miR-29c-3p target gene prediction and IPA analysis. Our focus extended to the number of neuronal branches, the excitatory synapse count, and locomotion-related pathways. Notably, GPR37, NPC1, and IREB2 emerged as potential target molecules for miR-29c-3p regulation, suggesting their involvement in the modulation of METH sensitization. Quantitative PCR confirmed the METH-induced aberrant expression of Gpr37, Npc1, and Ireb2 in the NAc of mice. Specifically, the over-expression of miR-29c-3p led to a significant reduction in the mRNA level of Gpr37, while the inhibition of miR-29c-3p resulted in a significant increase in the mRNA level of Gpr37, consistent with the regulatory principle of miRNAs modulating target gene expression. This suggests that miR-29c-3p potentially influences METH sensitization through its regulation of neuroplasticity. Our research indicates that miR-29c-3p plays a crucial role in regulating METH-induced sensitization, and it identified the potential molecular of miR-29c-3p in regulating METH-induced sensitization.

Attenuation of Age-Related Hearing Impairment in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice Treated with Fatty Acid Synthase Inhibitor CMS121

In the senescence-accelerated mouse prone 8 (SAMP8) mouse model, oxidative stress leads to premature senescence and age-related hearing impairment (ARHI). CMS121 inhibits oxytosis/ferroptosis by targeting fatty acid synthase. The aim of our study was to determine whether CMS121 is protective against ARHI in SAMP8 mice. Auditory brainstem responses (ABRs) were used to assess baseline hearing in sixteen 4-week-old female SAMP8 mice, which were divided into two cohorts. The control group was fed a vehicle diet, while the experimental group was fed a diet containing CMS121. ABRs were measured until 13 weeks of age. Cochlear immunohistochemistry was performed to analyze the number of paired ribbon-receptor synapses per inner hair cell (IHC). Descriptive statistics are provided with mean ± SEM. Two-sample t-tests were performed to compare hearing thresholds and paired synapse count across the two groups, with alpha = 0.05. Baseline hearing thresholds in the control group were statistically similar to those of the CMS121 group. At 13 weeks of age, the control group had significantly worse hearing thresholds at 12 kHz (56.5 vs. 39.8, p = 0.044) and 16 kHz (64.8 vs. 43.8, p = 0.040) compared to the CMS121 group. Immunohistochemistry showed a significantly lower synapse count per IHC in the control group (15.7) compared to the CMS121 group (18.4), p = 0.014. Our study shows a significant reduction in ABR threshold shifts and increased preservation of IHC ribbon synapses in the mid-range frequencies among mice treated with CMS121 compared to untreated mice.

Conditional Ablation of Glucocorticoid and Mineralocorticoid Receptors from Cochlear Supporting Cells Reveals Their Differential Roles for Hearing Sensitivity and Dynamics of Recovery from Noise-Induced Hearing Loss.

Endogenous glucocorticoids (GC) are known to modulate basic elements of cochlear physiology. These include both noise-induced injury and circadian rhythms. While GC signaling in the cochlea can directly influence auditory transduction via actions on hair cells and spiral ganglion neurons, evidence also indicates that GC signaling exerts effects via tissue homeostatic processes that can include effects on cochlear immunomodulation. GCs act at both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Most cell types in the cochlea express both receptors sensitive to GCs. The GR is associated with acquired sensorineural hearing loss (SNHL) through its effects on both gene expression and immunomodulatory programs. The MR has been associated with age-related hearing loss through dysfunction of ionic homeostatic balance. Cochlear supporting cells maintain local homeostatic requirements, are sensitive to perturbation, and participate in inflammatory signaling. Here, we have used conditional gene manipulation techniques to target Nr3c1 (GR) or Nr3c2 (MR) for tamoxifen-induced gene ablation in Sox9-expressing cochlear supporting cells of adult mice to investigate whether either of the receptors sensitive to GCs plays a role in protecting against (or exacerbating) noise-induced cochlear damage. We have selected mild intensity noise exposure to examine the role of these receptors related to more commonly experienced noise levels. Our results reveal distinct roles of these GC receptors for both basal auditory thresholds prior to noise exposure and during recovery from mild noise exposure. Prior to noise exposure, auditory brainstem responses (ABRs) were measured in mice carrying the floxed allele of interest and the Cre recombinase transgene, but not receiving tamoxifen injections (defined as control (no tamoxifen treatment), versus conditional knockout (cKO) mice, defined as mice having received tamoxifen injections. Results revealed hypersensitive thresholds to mid- to low-frequencies after tamoxifen-induced GR ablation from Sox9-expressing cochlear supporting cells compared to control (no tamoxifen) mice. GR ablation from Sox9-expressing cochlear supporting cells resulted in a permanent threshold shift in mid-basal cochlear frequency regions after mild noise exposure that produced only a temporary threshold shift in both control (no tamoxifen) f/fGR:Sox9iCre+ and heterozygous f/+GR:Sox9iCre+ tamoxifen-treated mice. A similar comparison of basal ABRs measured in control (no tamoxifen) and tamoxifen-treated, floxed MR mice prior to noise exposure indicated no difference in baseline thresholds. After mild noise exposure, MR ablation was initially associated with a complete threshold recovery at 22.6 kHz by 3 days post-noise. Threshold continued to shift to higher sensitivity over time such that by 30 days post-noise exposure the 22.6 kHz ABR threshold was 10 dB more sensitive than baseline. Further, MR ablation produced a temporary reduction in peak 1 neural amplitude one day post-noise. While supporting cell GR ablation trended towards reducing numbers of ribbon synapses, MR ablation reduced ribbon synapse counts but did not exacerbate noise-induced damage including synapse loss at the experimental endpoint. GR ablation from the targeted supporting cells increased the basal resting number of Iba1-positive (innate) immune cells (no noise exposure) and decreased the number of Iba1-positive cells seven days following noise exposure. MR ablation did not alter innate immune cell numbers at seven days post-noise exposure. Taken together, these findings support differential roles of cochlear supporting cell MR and GR expression at basal, resting conditions and especially during recovery from noise exposure.

Predicting synapse counts in living humans by combining computational models with auditory physiology.

Aging, noise exposure, and ototoxic medications lead to cochlear synapse loss in animal models. As cochlear function is highly conserved across mammalian species, synaptopathy likely occurs in humans as well. Synaptopathy is predicted to result in perceptual deficits including tinnitus, hyperacusis, and difficulty understanding speech-in-noise. The lack of a method for diagnosing synaptopathy in living humans hinders studies designed to determine if noise-induced synaptopathy occurs in humans, identify the perceptual consequences of synaptopathy, or test potential drug treatments. Several physiological measures are sensitive to synaptopathy in animal models including auditory brainstem response (ABR) wave I amplitude. However, it is unclear how to translate these measures to synaptopathy diagnosis in humans. This work demonstrates how a human computational model of the auditory periphery, which can predict ABR waveforms and distortion product otoacoustic emissions (DPOAEs), can be used to predict synaptic loss in individual human participants based on their measured DPOAE levels and ABR wave I amplitudes. Lower predicted synapse numbers were associated with advancing age, higher noise exposure history, increased likelihood of tinnitus, and poorer speech-in-noise perception. These findings demonstrate the utility of this modeling approach in predicting synapse counts from physiological data in individual human subjects.

Large-scale phenotyping of ABR P1-N1 amplitudes before and after exposure to noise in 69 strains of mice.

ABR wave I amplitude represents the synapse of auditory nerve fibers with the inner hair cell and is highly correlated with synapse counts. Cochlear synaptopathy, the loss of synaptic connections between inner hair cells and auditory nerve fibers, has been well-demonstrated in animal models of noise-induced hearing loss. The peak-to-peak wave I amplitude was determined at baseline and 2weeks after noise exposure. We determined the ABR wave I amplitude at 80dB SPL at the frequencies of 8, 12, 16, 24, and 32kHz. A total of 69 strains (1-8 mice/strain) were analyzed. A statistically significant post-noise reduction in wave I amplitude was observed in all the tested frequencies (p < 0.00001). We identify distinct patterns of noise susceptibility and make this complete phenotypic dataset available for general use. This data establishes a new resource for the study of NIHL in mice and we hope this database will be a useful tool to expand the research in this field.

Synaptic migration and reorganization after noise exposure suggests regeneration in a mature mammalian cochlea

Overexposure to intense noise can destroy the synapses between auditory nerve fibers and their hair cell targets without destroying the hair cells themselves. In adult mice, this synaptopathy is immediate and largely irreversible, whereas, in guinea pigs, counts of immunostained synaptic puncta can recover with increasing post-exposure survival. Here, we asked whether this recovery simply reflects changes in synaptic immunostaining, or whether there is actual retraction and extension of neurites and/or synaptogenesis. Analysis of the numbers, sizes and spatial distribution of pre- and post-synaptic markers on cochlear inner hair cells, in guinea pigs surviving from 1 day to 6 months after a synaptopathic exposure, shows dramatic synaptic re-organization during the recovery period in which synapse counts recover from 16 to 91% of normal in the most affected regions. Synaptic puncta move all over the hair cell membrane during recovery, translocating far from their normal positions at the basolateral pole, and auditory-nerve terminals extend towards the hair cell’s apical end to re-establish contact with them. These observations provide stronger evidence for spontaneous neural regeneration in a mature mammalian cochlea than can be inferred from synaptic counts alone.

Ultrastructural GABA immunogold labeling in the substantia nigra pars reticulata of kindled genetic absence epilepsy rats

ABSTRACT Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a well-known animal model of absence epilepsy and they are resistant to electrical kindling stimulations. The present study aimed to examine possible differences in gamma-aminobutyric acid (GABA) levels and synapse counts in the substantia nigra pars reticulata anterior (SNRa) and posterior (SNRp) regions between GAERS and Wistar rats receiving kindling stimulations. Animals in the kindling group either received six stimulations in the amygdala and had grade 2 seizures or they were kindled, having grade five seizures. Rats were decapitated one hour after the last stimulation. SNR regions were obtained after vibratome sectioning of the brain tissue. GABA immunoreactivity was detected by immunogold method and synapses were counted. Sections were observed by transmission electron microscope and analyzed by Image J program. GABA density in the SNRa region of fully kindled GAERS and Wistar groups increased significantly compared to that of their corresponding grade 2 groups. The number of synapses increased significantly in kindled and grade 2 GAERS groups, compared to kindled and grade 2 Wistar groups, respectively, in the SNRa region. GABA density in the SNRp region of kindled GAERS group increased significantly compared to that of GAERS grade 2 group. In the SNRp region, both kindled and grade 2 GAERS groups were found to have increased number of synapses compared to that of GAERS control group. We concluded that both SNRa and SNRp regions may be important in modulating resistance of GAERS to kindling stimulations.

Systematic Quantification of Synapses in Primary Neuronal Culture.

SummaryMost neurological disorders display impaired synaptic connectivity. Hence, modulation of synapse formation may have therapeutic relevance. However, the high density and small size of synapses complicate their quantification. To improve synapse-oriented screens, we analyzed the labeling performance of synapse-targeting antibodies on neuronal cell cultures using segmentation-independent image analysis based on sliding window correlation. When assessing pairwise colocalization, a common readout for mature synapses, overlap was incomplete and confounded by spurious signals. To circumvent this, we implemented a proximity ligation-based approach that only leads to a signal when two markers are sufficiently close. We applied this approach to different marker combinations and demonstrate its utility for detecting synapse density changes in healthy and compromised cultures. Thus, segmentation-independent analysis and exploitation of resident protein proximity increases the sensitivity of synapse quantifications in neuronal cultures and represents a valuable extension to the analytical toolset for in vitro synapse screens.

Nicotinamide riboside protects noise-induced hearing loss by recovering the hair cell ribbon synapses

ObjectiveNicotinamide riboside (NR) has been proved to protect the hearing. To achieve animal models of temporary threshold shift (TTS) and permanent threshold shift (PTS) respectively, evaluate the dynamic change of ribbon synapse before and after NR administration. MethodsMice were divided into control group, noise exposure (NE) group and NR group. The noise was exposed to NE and NR group, and NR was injected before noise exposure. Auditory brainstem response (ABR), ribbon synapse count and cochlear morphology were tested, as well as the concentration of hydrogen peroxide (H2O2) and ATP. ResultsRibbon synapse count decrease with the intensity of noise exposure, and the cochlear morphology remains stable during TTS and was damaged during PTS. NR promotes the oxidation resistance to protect the synapse and the inner ear morphology. ConclusionOur findings suggest that TTS mice are more vulnerable to noise, and NR can promote the recovery of the synapse count to protect the animals’ hearing.

Network Models Predict That Pyramidal Neuron Hyperexcitability and Synapse Loss in the dlPFC Lead to Age-Related Spatial Working Memory Impairment in Rhesus Monkeys.

Behavioral studies have shown spatial working memory impairment with aging in several animal species, including humans. Persistent activity of layer 3 pyramidal dorsolateral prefrontal cortex (dlPFC) neurons during delay periods of working memory tasks is important for encoding memory of the stimulus. In vitro studies have shown that these neurons undergo significant age-related structural and functional changes, but the extent to which these changes affect neural mechanisms underlying spatial working memory is not understood fully. Here, we confirm previous studies showing impairment on the Delayed Recognition Span Task in the spatial condition (DRSTsp), and increased in vitro action potential firing rates (hyperexcitability), across the adult life span of the rhesus monkey. We use a bump attractor model to predict how empirically observed changes in the aging dlPFC affect performance on the Delayed Response Task (DRT), and introduce a model of memory retention in the DRSTsp. Persistent activity—and, in turn, cognitive performance—in both models was affected much more by hyperexcitability of pyramidal neurons than by a loss of synapses. Our DRT simulations predict that additional changes to the network, such as increased firing of inhibitory interneurons, are needed to account for lower firing rates during the DRT with aging reported in vivo. Synaptic facilitation was an essential feature of the DRSTsp model, but it did not compensate fully for the effects of the other age-related changes on DRT performance. Modeling pyramidal neuron hyperexcitability and synapse loss simultaneously led to a partial recovery of function in both tasks, with the simulated level of DRSTsp impairment similar to that observed in aging monkeys. This modeling work integrates empirical data across multiple scales, from synapse counts to cognitive testing, to further our understanding of aging in non-human primates.

Neuronal Morphology and Synapse Count in the Nematode Worm.

The somatic nervous system of the nematode worm Caenorhabditis elegans is a model for understanding the physical characteristics of the neurons and their interconnections. Its neurons show high variation in morphological attributes. This study investigates the relationship of neuronal morphology to the number of synapses per neuron. Morphology is also examined for any detectable association with neuron cell type or ganglion membership.

Neuron density fundamentally relates to architecture and connectivity of the primate cerebral cortex

Studies of structural brain connectivity have revealed many intriguing features of complex cortical networks. To advance integrative theories of cortical organization, an understanding is required of how connectivity interrelates with other aspects of brain structure. Recent studies have suggested that interareal connectivity may be related to a variety of macroscopic as well as microscopic architectonic features of cortical areas. However, it is unclear how these features are inter-dependent and which of them most strongly and fundamentally relate to structural corticocortical connectivity. Here, we systematically investigated the relation of a range of microscopic and macroscopic architectonic features of cortical organization, namely layer III pyramidal cell soma cross section, dendritic synapse count, dendritic synapse density and dendritic tree size as well as area neuron density, to multiple properties of cortical connectivity, using a comprehensive, up-to-date structural connectome of the primate brain. Importantly, relationships were investigated by multi-variate analyses to account for the interrelations of features. Of all considered factors, the classical architectonic parameter of neuron density most strongly and consistently related to essential features of cortical connectivity (existence and laminar patterns of projections, area degree), and in conjoint analyses largely abolished effects of cellular morphological features. These results confirm neuron density as a central architectonic indicator of the primate cerebral cortex that is closely related to essential aspects of brain connectivity and is also highly indicative of further features of the architectonic organization of cortical areas, such as the considered cellular morphological measures. Our findings integrate several aspects of cortical micro- and macroscopic organization, with implications for cortical development and function.

Use of non-invasive measures to predict cochlear synapse counts

Cochlear synaptopathy, the loss of synaptic connections between inner hair cells (IHCs) and auditory nerve fibers, has been documented in animal models of aging, noise, and ototoxic drug exposure, three common causes of acquired sensorineural hearing loss in humans. In each of these models, synaptopathy begins prior to changes in threshold sensitivity or loss of hair cells; thus, this underlying injury can be hidden behind a normal threshold audiogram. Since cochlear synaptic loss cannot be directly confirmed in living humans, non-invasive assays will be required for diagnosis. In animals with normal auditory thresholds, the amplitude of wave 1 of the auditory brainstem response (ABR) is highly correlated with synapse counts. However, synaptopathy can also co-occur with threshold elevation, complicating the use of the ABR alone as a diagnostic measure. Using an age-graded series of mice and a partial least squares regression approach to model structure-function relationships, this study shows that the combination of a small number of ABR and distortion product otoacoustic emission (DPOAE) measurements can predict synaptic ribbon counts at various cochlear frequencies to within 1–2 synapses per IHC of their true value. In contrast, the model, trained using the age-graded series of mice, overpredicted synapse counts in a small sample of young noise-exposed mice, perhaps due to differences in the underlying pattern of damage between aging and noise-exposed mice. These results provide partial validation of a noninvasive approach to identify synaptic/neuronal loss in humans using ABRs and DPOAEs.

Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits

BackgroundExposure of the developing brain to propofol results in cognitive deficits. Recent data suggest that inhibition of neuronal apoptosis does not prevent cognitive defects, suggesting mechanisms other than neuronal apoptosis play a role in anaesthetic neurotoxicity. Proper neuronal growth during development is dependent upon growth cone morphology and axonal transport. Propofol modulates actin dynamics in developing neurones, causes RhoA-dependent depolymerisation of actin, and reduces dendritic spines and synapses. We hypothesised that RhoA inhibition prevents synaptic loss and subsequent cognitive deficits. The present study tested whether RhoA inhibition with the botulinum toxin C3 (TAT-C3) prevents propofol-induced synapse and neurite loss, and preserves cognitive function. MethodsRhoA activation, growth cone morphology, and axonal transport were measured in neonatal rat neurones (5–7 days in vitro) exposed to propofol. Synapse counts (electron microscopy), dendritic arborisation (Golgi–Cox), and network connectivity were measured in mice (age 28 days) previously exposed to propofol at postnatal day 5–7. Memory was assessed in adult mice (age 3 months) previously exposed to propofol at postnatal day 5–7. ResultsPropofol increased RhoA activation, collapsed growth cones, and impaired retrograde axonal transport of quantum dot-labelled brain-derived neurotrophic factor, all of which were prevented with TAT-C3. Adult mice previously treated with propofol had decreased numbers of total hippocampal synapses and presynaptic vesicles, reduced hippocampal dendritic arborisation, and infrapyramidal mossy fibres. These mice also exhibited decreased hippocampal-dependent contextual fear memory recall. All anatomical and behavioural changes were prevented with TAT-C3 pre-treatment. ConclusionInhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits.

Studying the role of axon fasciculation during development in a computational model of the Xenopus tadpole spinal cord

During nervous system development growing axons can interact with each other, for example by adhering together in order to produce bundles (fasciculation). How does such axon-axon interaction affect the resulting axonal trajectories, and what are the possible benefits of this process in terms of network function? In this paper we study these questions by adapting an existing computational model of the development of neurons in the Xenopus tadpole spinal cord to include interactions between axons. We demonstrate that even relatively weak attraction causes bundles to appear, while if axons weakly repulse each other their trajectories diverge such that they fill the available space. We show how fasciculation can help to ensure axons grow in the correct location for proper network formation when normal growth barriers contain gaps, and use a functional spiking model to show that fasciculation allows the network to generate reliable swimming behaviour even when overall synapse counts are artificially lowered. Although we study fasciculation in one particular organism, our approach to modelling axon growth is general and can be widely applied to study other nervous systems.

Pitfalls of using confocal-microscopy based automated quantification of synaptic complexes in honeybee mushroom bodies (response to Peng and Yang 2016)

A recent study by Peng and Yang in Scientific Reports using confocal-microscopy based automated quantification of anti-synapsin labeled microglomeruli in the mushroom bodies of honeybee brains reports potentially incorrect numbers of microglomerular densities. Whereas several previous studies using visually supervised or automated counts from confocal images and analyses of serial 3D electron-microscopy data reported consistent numbers of synaptic complexes per volume, Peng and Yang revealed extremely low numbers differing by a factor of 18 or more from those obtained in visually supervised counts, and by a factor 22–180 from numbers in two other studies using automated counts. This extreme discrepancy is especially disturbing as close comparison of raw confocal images of anti-synapsin labeled whole-mount brain preparations are highly similar across these studies. We conclude that these discrepancies may reside in potential misapplication of confocal imaging followed by erroneous use of automated image analysis software. Consequently, the reported microglomerular densities during maturation and after manipulation by insecticides require validation by application of appropriate confocal imaging methods and analyses tools that rely on skilled observers. We suggest several improvements towards more reliable or standardized automated or semi-automated synapse counts in whole mount preparations of insect brains.

Ca2+-binding protein 2 inhibits Ca2+-channel inactivation in mouse inner hair cells

Ca2+-binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca2+ channels of type 1.3 (CaV1.3) and is defective in human autosomal-recessive deafness 93 (DFNB93). Here, we report a newly identified mutation in CABP2 that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting from CABP2 loss of function, we disrupted Cabp2 in mice (Cabp2LacZ/LacZ ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs). Cabp2LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from Cabp2LacZ/LacZ IHCs revealed enhanced Ca2+-channel inactivation. The voltage dependence of activation and the number of Ca2+ channels appeared normal in Cabp2LacZ/LacZ mice, as were ribbon synapse counts. Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates. We propose that CaBP2 inhibits CaV1.3 Ca2+-channel inactivation, and thus sustains the availability of CaV1.3 Ca2+ channels for synaptic sound encoding. Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.

Coding deficits in hidden hearing loss induced by noise: the nature and impacts.

Hidden hearing refers to the functional deficits in hearing without deterioration in hearing sensitivity. This concept is proposed based upon recent finding of massive noise-induced damage on ribbon synapse between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in the cochlea without significant permanent threshold shifts (PTS). Presumably, such damage may cause coding deficits in auditory nerve fibers (ANFs). However, such deficits had not been detailed except that a selective loss of ANFs with low spontaneous rate (SR) was reported. In the present study, we investigated the dynamic changes of ribbon synapses and the coding function of ANF single units in one month after a brief noise exposure that caused a massive damage of ribbon synapses but no PTS. The synapse count and functional response measures indicates a large portion of the disrupted synapses were re-connected. This is consistent with the fact that the change of SR distribution due to the initial loss of low SR units is recovered quickly. However, ANF coding deficits were developed later with the re-establishment of the synapses. The deficits were found in both intensity and temporal processing, revealing the nature of synaptopathy in hidden hearing loss.

Dexmedetomidine protects spatial learning and memory ability in rats.

The authors tested the hypothesis that combined use of dexmedetomidine on fetal rats during isoflurane exposure in maternal anesthesia can attenuate the abnormal spatial learning and memory abilities in adults via the renin-angiotensin-aldosterone system. Fifty timed-pregnancy rats were randomly assigned to five groups (Dex+Iso, Sal+Iso, Sal+Oxy, Dex+Oxy, and a control group ) on embryonic day 14 to receive five different dispositions, i.e. combined injection of dexmedetomidine (Dex) or saline (Sal) and inhalation of isoflurane (Iso), oxygen (Oxy), or normal air for 4 h (n = 10). The latency time(s) from day 1 to day 4 all showed a decreasing tendency in all four groups. The synaptic count of the Sal+Iso group was significantly lower than the Control group (p < 0.05), suggesting that severe neurodegeneration occurred under the influence of fetal isoflurane exposure. In contrast, the synapse count of the Dex+Iso group was near to that of Control group. The rats are protected in neurodevelopmental, normal development. Combine use of dexmedetomidine during exposure to isoflurane in utero during middle-pregnancy can attenuate the impairment of spatial learning and memory abilities for the rats in adulthood.