PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (1007449)

Clipboard (0)
None

Related Articles

1.  A Role for Short-Term Synaptic Facilitation and Depression in the Processing of Intensity Information in the Auditory Brain Stem 
Journal of Neurophysiology  2007;97(4):2863-2874.
The nature of the synaptic connection from the auditory nerve onto the cochlear nucleus neurons has a profound impact on how sound information is transmitted. Short-term synaptic plasticity, by dynamically modulating synaptic strength, filters information contained in the firing patterns. In the sound-localization circuits of the brain stem, the synapses of the timing pathway are characterized by strong short-term depression. We investigated the short-term synaptic plasticity of the inputs to the bird’s cochlear nucleus angularis (NA), which encodes intensity information, by using chick embryonic brain slices and trains of electrical stimulation. These excitatory inputs expressed a mixture of short-term facilitation and depression, unlike those in the timing nuclei that only depressed. Facilitation and depression at NA synapses were balanced such that postsynaptic response amplitude was often maintained throughout the train at high firing rates (>100 Hz). The steady-state input rate relationship of the balanced synapses linearly conveyed rate information and therefore transmits intensity information encoded as a rate code in the nerve. A quantitative model of synaptic transmission could account for the plasticity by including facilitation of release (with a time constant of ~40 ms), and a two-step recovery from depression (with one slow time constant of ~8 s, and one fast time constant of ~20 ms). A simulation using the model fit to NA synapses and auditory nerve spike trains from recordings in vivo confirmed that these synapses can convey intensity information contained in natural train inputs.
doi:10.1152/jn.01030.2006
PMCID: PMC3268177  PMID: 17251365
2.  Short-Term Synaptic Depression Is Topographically Distributed in the Cochlear Nucleus of the Chicken 
The Journal of Neuroscience  2014;34(4):1314-1324.
In the auditory system, sounds are processed in parallel frequency-tuned circuits, beginning in the cochlea. Activity of auditory nerve fibers reflects this frequency-specific topographic pattern, known as tonotopy, and imparts frequency tuning onto their postsynaptic target neurons in the cochlear nucleus. In birds, cochlear nucleus magnocellularis (NM) neurons encode the temporal properties of acoustic stimuli by “locking” discharges to a particular phase of the input signal. Physiological specializations exist in gradients corresponding to the tonotopic axis in NM that reflect the characteristic frequency (CF) of their auditory nerve fiber inputs. One feature of NM neurons that has not been investigated across the tonotopic axis is short-term synaptic plasticity. NM offers a rather homogeneous population of neurons with a distinct topographical distribution of synaptic properties that is ideal for the investigation of specialized synaptic plasticity. Here we demonstrate for the first time that short-term synaptic depression (STD) is expressed topographically, where unitary high CF synapses are more robust with repeated stimulation. Correspondingly, high CF synapses drive spiking more reliably than their low CF counterparts. We show that postsynaptic AMPA receptor desensitization does not contribute to the observed difference in STD. Further, rate of recovery from depression, a presynaptic property, does not differ tonotopically. Rather, we show that another presynaptic feature, readily releasable pool (RRP) size, is tonotopically distributed and inversely correlated with vesicle release probability. Mathematical model results demonstrate that these properties of vesicle dynamics are sufficient to explain the observed tonotopic distribution of STD.
doi:10.1523/JNEUROSCI.3073-13.2014
PMCID: PMC3898291  PMID: 24453322
tonotopy; topographic map; synaptic plasticity; short-term synaptic depression; release probability; readily releasable pool
3.  Evidence That Rapid Vesicle Replenishment of the Synaptic Ribbon Mediates Recovery from Short-Term Adaptation at the Hair Cell Afferent Synapse 
We have employed both in vitro patch clamp recordings of hair cell synaptic vesicle fusion and in vivo single unit recording of cochlear nerve activity to study, at the same synapse, the time course, control, and physiological significance of readily releasable pool dynamics. Exocytosis of the readily releasable pool was fast, saturating in less than 50 ms, and recovery was also rapid, regaining 95% of its initial amplitude following a 200-ms period of repolarization. Longer depolarizations (greater than 250 ms) yielded a second, slower kinetic component of exocytosis. Both the second component of exocytosis and recovery of the readily releasable pool were blocked by the slow calcium buffer, EGTA. Sound-evoked afferent synaptic activity adapted and recovered with similar time courses as readily releasable pool exhaustion and recovery. Comparison of readily releasable pool amplitude, capture distances of calcium buffers, and number of vesicles tethered to the synaptic ribbon suggested that readily releasable pool dynamics reflect the depletion of release-ready vesicles tethered to the synaptic ribbon and the reloading of the ribbon with vesicles from the cytoplasm. Thus, we submit that rapid recovery of the cochlear hair cell afferent fiber synapse from short-term adaptation depends on the timely replenishment of the synaptic ribbon with vesicles from a cytoplasmic pool. This apparent rapid reloading of the synaptic ribbon with vesicles underscores important functional differences between synaptic ribbons in the auditory and visual systems.
doi:10.1007/s10162-004-5003-8
PMCID: PMC2504567  PMID: 15675002
hair cell; exocytosis; adaptation; synaptic ribbon; synaptic vesicle; cochlea
4.  Heterogeneous kinetics and pharmacology of synaptic inhibition in the chick auditory brainstem 
Identification of shared features between avian and mammalian auditory brainstem circuits has provided much insight into the mechanisms underlying early auditory processing. However, previous studies have highlighted an apparent difference in inhibitory systems; synaptic inhibition is thought to be slow and GABAergic in birds, but to have fast kinetics and be predominantly glycinergic in mammals. Using patch-clamp recordings in chick brainstem slices, we found this distinction is not exclusively true. Consistent with previous work, inhibitory postsynaptic currents (IPSCs) in nucleus magnocellularis (NM) were slow and mediated by GABAA receptors. However, IPSCs in nucleus laminaris (NL) and a subset of neurons in nucleus angularis (NA) had rapid time courses two to three-fold faster than those in NM. Further, we found IPSCs in NA were mediated by both glycine and GABAA receptors, demonstrating for the first time a role for fast glycinergic transmission in the avian auditory brainstem. Although NM, NL and NA have unique roles in auditory processing, the majority of inhibitory input to each nucleus arises from the same source, ipsilateral superior olivary nucleus (SON). Our results demonstrate remarkable diversity of inhibitory transmission among the avian brainstem nuclei and suggest differential glycine and GABAA receptor activity tailors inhibition to the specific functional roles of NM, NL, and NA despite common SON input. We additionally observed that glycinergic/GABAergic activity in NA was usually depolarizing and could elicit spiking activity in NA neurons. Because NA projects to SON, these excitatory effects may influence the recruitment of inhibitory activity in the brainstem nuclei.
doi:10.1523/JNEUROSCI.0103-09.2009
PMCID: PMC2894706  PMID: 19641125
Auditory; GABA; Glycine; Patch Clamp; Inhibition; Synapse
5.  Inhibitory glycinergic neurotransmission in the mammalian auditory brainstem upon prolonged stimulation: short-term plasticity and synaptic reliability 
Short-term plasticity plays a key role in synaptic transmission and has been extensively investigated for excitatory synapses. Much less is known about inhibitory synapses. Here we analyze the performance of glycinergic connections between the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO) in the auditory brainstem, where high spike rates as well as fast and precise neurotransmission are hallmarks. Analysis was performed in acute mouse slices shortly after hearing onset (postnatal day (P)11) and 8 days later (P19). Stimulation was done at 37°C with 1–400 Hz for 40 s. Moreover, in a novel approach named marathon experiments, a very prolonged stimulation protocol was employed, comprising 10 trials of 1-min challenge and 1-min recovery periods at 50 and 1 Hz, respectively, thus lasting up to 20 min and amounting to >30,000 stimulus pulses. IPSC peak amplitudes displayed short-term depression (STD) and synaptic attenuation in a frequency-dependent manner. No facilitation was observed. STD in the MNTB-LSO connections was less pronounced than reported in the upstream calyx of Held-MNTB connections. At P11, the STD level and the failure rate were slightly lower within the ms-to-s range than at P19. During prolonged stimulation periods lasting 40 s, P19 connections sustained virtually failure-free transmission up to frequencies of 100 Hz, whereas P11 connections did so only up to 50 Hz. In marathon experiments, P11 synapses recuperated reproducibly from synaptic attenuation during all recovery periods, demonstrating a robust synaptic machinery at hearing onset. At 26°C, transmission was severely impaired and comprised abnormally high amplitudes after minutes of silence, indicative of imprecisely regulated vesicle pools. Our study takes a fresh look at synaptic plasticity and stability by extending conventional stimulus periods in the ms-to-s range to minutes. It also provides a framework for future analyses of synaptic plasticity.
doi:10.3389/fncir.2014.00014
PMCID: PMC3948056  PMID: 24653676
synaptic fidelity; fast-spiking cells; short-term depression; inhibitory postsynaptic currents; synaptic attenuation; lateral superior olive; medial nucleus of the trapezoid body; high-frequency neurotransmission
6.  Relative roles of different mechanisms of depression at the mouse endbulb of Held 
Journal of neurophysiology  2008;99(5):2510-2521.
Several mechanisms can underlie short-term synaptic depression, including vesicle depletion, receptor desensitization, and changes in presynaptic release probability. To determine which mechanisms affect depression under physiological conditions, we studied the synapse formed by auditory nerve fibers onto bushy cells in the anteroventral cochlear nucleus (the “endbulb of Held”) using voltage-clamp recordings of brain slices from P15–21 mice near physiological temperatures. Depression of both AMPA and NMDA EPSCs showed two phases of recovery. The fast component of depression for the AMPA EPSC was eliminated by cyclothiazide and aniracetam, suggesting it results from desensitization. The fast component of depression for the NMDA EPSC was reduced by the low-affinity antagonist L-AP5, suggesting it results from saturation. The remaining depression in AMPA and NMDA components is identical and therefore presynaptic in origin. It is likely to result from presynaptic vesicle depletion. Recovery from depression after trains of activity was slowed by the application of EGTA-AM, suggesting that the endbulb has a residual-calcium-dependent form of recovery. We developed a model that incorporates depletion, desensitization, and calcium-dependent recovery. This model replicated experimental findings over a range of experimental conditions. The model further indicated that desensitization plays only a minor role during prolonged activity, in large part because presynaptic release is so depleted. Thus, depletion appears to be the dominant mechanism of depression at the endbulb during normal activity. Furthermore, calcium-dependent recovery at the endbulb is critical to prevent complete run-down during high activity and to preserve the reliability of information transmission.
doi:10.1152/jn.01293.2007
PMCID: PMC2905879  PMID: 18367696
Synapse; Depression; Saturation; Desensitization; Endbulb; Modeling
7.  Recovery from short-term depression and facilitation is ultrafast and Ca2+-dependent at auditory hair cell synapses 
Short-term facilitation and depression coexist at many CNS synapses. Facilitation, however, has not been fully characterized at hair cell synapses. Using paired recordings and membrane capacitance measurements we find that paired-pulse plasticity at an adult frog auditory hair cell synapse depends on pulse duration and inter-pulse intervals. For short 20 ms depolarizing pulses, and inter-pulse intervals between 15 to 50 ms, facilitation occurred when hair cells were held at −90 mV. However, hair cells held at −60 mV displayed only paired-pulse depression. Facilitation was dependent on residual free Ca2+ levels because it was greatly reduced by the Ca2+ buffers EGTA and BAPTA. Furthermore, low external Ca2+ augmented facilitation, whereas depression was augmented by high external Ca2+, consistent with depletion of a small pool of fast releasing synaptic vesicles. Recovery from depression had a double-exponential time course with a fast component that may reflect the rapid replenishment of a depleted vesicle pool. We suggest that hair cells held at more depolarized in vivo-like resting membrane potentials have a tonic influx of Ca2+; they are thus in a dynamic state of continuous vesicle release, pool depletion and replenishment. Further Ca2+ influx during paired-pulse stimuli then leads to depression. However, at membrane potentials of −90 mV ongoing release and pool depletion are minimized, so facilitation is revealed at time intervals when rapid vesicle pool replenishment occurs. Finally, we propose that vesicle pool replenishment kinetics is not rate-limited by vesicle endocytosis, which is too slow to influence the rapid pool replenishment process.
doi:10.1523/JNEUROSCI.5453-10.2011
PMCID: PMC3090423  PMID: 21490209
auditory afferent fibers; paired-pulse depression; paired-pulse facilitation; short-term plasticity; membrane capacitance; excitatory postsynaptic current
8.  Long-Term Evolution of Brainstem Electrical Evoked Responses to Sound after Restricted Ablation of the Auditory Cortex 
PLoS ONE  2013;8(9):e73585.
Introduction
This study aimed to assess the top-down control of sound processing in the auditory brainstem of rats. Short latency evoked responses were analyzed after unilateral or bilateral ablation of auditory cortex. This experimental paradigm was also used towards analyzing the long-term evolution of post-lesion plasticity in the auditory system and its ability to self-repair.
Method
Auditory cortex lesions were performed in rats by stereotactically guided fine-needle aspiration of the cerebrocortical surface. Auditory Brainstem Responses (ABR) were recorded at post-surgery day (PSD) 1, 7, 15 and 30. Recordings were performed under closed-field conditions, using click trains at different sound intensity levels, followed by statistical analysis of threshold values and ABR amplitude and latency variables. Subsequently, brains were sectioned and immunostained for GAD and parvalbumin to assess the location and extent of lesions accurately.
Results
Alterations in ABR variables depended on the type of lesion and post-surgery time of ABR recordings. Accordingly, bilateral ablations caused a statistically significant increase in thresholds at PSD1 and 7 and a decrease in waves amplitudes at PSD1 that recover at PSD7. No effects on latency were noted at PSD1 and 7, whilst recordings at PSD15 and 30 showed statistically significant decreases in latency. Conversely, unilateral ablations had no effect on auditory thresholds or latencies, while wave amplitudes only decreased at PSD1 strictly in the ipsilateral ear.
Conclusion
Post-lesion plasticity in the auditory system acts in two time periods: short-term period of decreased sound sensitivity (until PSD7), most likely resulting from axonal degeneration; and a long-term period (up to PSD7), with changes in latency responses and recovery of thresholds and amplitudes values. The cerebral cortex may have a net positive gain on the auditory pathway response to sound.
doi:10.1371/journal.pone.0073585
PMCID: PMC3774800  PMID: 24066057
9.  synaptojanin1 Is Required for Temporal Fidelity of Synaptic Transmission in Hair Cells 
PLoS Genetics  2009;5(5):e1000480.
To faithfully encode mechanosensory information, auditory/vestibular hair cells utilize graded synaptic vesicle (SV) release at specialized ribbon synapses. The molecular basis of SV release and consequent recycling of membrane in hair cells has not been fully explored. Here, we report that comet, a gene identified in an ENU mutagenesis screen for zebrafish larvae with vestibular defects, encodes the lipid phosphatase Synaptojanin 1 (Synj1). Examination of mutant synj1 hair cells revealed basal blebbing near ribbons that was dependent on Cav1.3 calcium channel activity but not mechanotransduction. Synaptojanin has been previously implicated in SV recycling; therefore, we tested synaptic transmission at hair-cell synapses. Recordings of post-synaptic activity in synj1 mutants showed relatively normal spike rates when hair cells were mechanically stimulated for a short period of time at 20 Hz. In contrast, a sharp decline in the rate of firing occurred during prolonged stimulation at 20 Hz or stimulation at a higher frequency of 60 Hz. The decline in spike rate suggested that fewer vesicles were available for release. Consistent with this result, we observed that stimulated mutant hair cells had decreased numbers of tethered and reserve-pool vesicles in comparison to wild-type hair cells. Furthermore, stimulation at 60 Hz impaired phase locking of the postsynaptic activity to the mechanical stimulus. Following prolonged stimulation at 60 Hz, we also found that mutant synj1 hair cells displayed a striking delay in the recovery of spontaneous activity. Collectively, the data suggest that Synj1 is critical for retrieval of membrane in order to maintain the quantity, timing of fusion, and spontaneous release properties of SVs at hair-cell ribbon synapses.
Author Summary
Ribbon synapses are found in the ear and eye and facilitate the transmission of sensory information to the brain. In hair cells of the ear, the molecules required for ribbon function have not been fully explored. Zebrafish are ideal for investigating molecular components of these specialized synapses because of the ability to study ribbon function using genetic, cellular, and physiological methods. Here, we explore the role of the lipid phosphatase Synaptojanin at the hair cell synapse. Synaptojanin has been previously implicated in synaptic vesicle recycling in conventional synapses, and we also find that the number of synaptic vesicles are reduced in mutant synaptojanin hair cells. Mutant synaptojanin larvae have obvious equilibrium defects, and our electrophysiological recordings revealed that synaptic transmission from hair cells to neurons projecting to the brain is impaired in terms of both rate and accuracy. When stimulated at high frequency or for prolonged periods, mutant synaptojanin hair cells release vesicles out of phase with mechanical stimuli, thus compromising the transfer of sensory information to the brain.
doi:10.1371/journal.pgen.1000480
PMCID: PMC2673039  PMID: 19424431
10.  Short Term Synaptic Depression Imposes a Frequency Dependent Filter on Synaptic Information Transfer 
PLoS Computational Biology  2012;8(6):e1002557.
Depletion of synaptic neurotransmitter vesicles induces a form of short term depression in synapses throughout the nervous system. This plasticity affects how synapses filter presynaptic spike trains. The filtering properties of short term depression are often studied using a deterministic synapse model that predicts the mean synaptic response to a presynaptic spike train, but ignores variability introduced by the probabilistic nature of vesicle release and stochasticity in synaptic recovery time. We show that this additional variability has important consequences for the synaptic filtering of presynaptic information. In particular, a synapse model with stochastic vesicle dynamics suppresses information encoded at lower frequencies more than information encoded at higher frequencies, while a model that ignores this stochasticity transfers information encoded at any frequency equally well. This distinction between the two models persists even when large numbers of synaptic contacts are considered. Our study provides strong evidence that the stochastic nature neurotransmitter vesicle dynamics must be considered when analyzing the information flow across a synapse.
Author Summary
Neurons communicate through electro-chemical connections called synapses. Action potentials in a presynaptic neuron cause neurotransmitter vesicles to release their contents which then bind to nearby receptors on a postsynaptic neuron's membrane, transiently altering its conductance. After it is released, the replacement of a neurotransmitter vesicle takes time and the depletion of vesicles can prevent subsequent action potentials from eliciting a postsynaptic response, an effect that represents a form of short term synaptic depression. When a vesicle is available for release, an action potential elicits its release probabilistically and depleted vesicles are replenished randomly in time, making the transmission of presynaptic signals inherently unreliable. We analyze a mathematical model of vesicle release and recovery to understand how signals encoded in sequences of presynaptic action potentials are reflected in the fluctuations of a postsynaptic neuron's conductance. We find that slow modulations in the rate of presynaptic action potentials are more difficult for a postsynaptic neuron to detect than faster modulations. This phenomenon is only observed when randomness in vesicle release and replacement is taken into account. Thus, by including stochasticity in the workings of synaptic dynamics we give new qualitative understanding to how information is transferred in the nervous system.
doi:10.1371/journal.pcbi.1002557
PMCID: PMC3380957  PMID: 22737062
11.  Developmental Changes in Short-Term Plasticity at the Rat Calyx of Held Synapse 
The calyx of Held synapse of the medial nucleus of the trapezoid body functions as a relay synapse in the auditory brainstem. In vivo recordings have shown that this synapse displays low release probability and that the average size of synaptic potentials does not depend on recent history. We used a ventral approach to make in vivo extracellular recordings from the calyx of Held synapse in rats aged postnatal day 4 (P4) to P29 to study the developmental changes that allow this synapse to function as a relay. Between P4 and P8, we observed evidence for the presence of large short-term depression, which was counteracted by short-term facilitation at short intervals. Major changes occurred in the last few days before the onset of hearing for air-borne sounds, which happened at P13. The bursting pattern changed into a primary-like pattern, the amount of depression and facilitation decreased strongly, and the decay of facilitation became much faster. Whereas short-term plasticity was the most important cause of variability in the size of the synaptic potentials in immature animals, its role became minor around hearing onset and afterward. Similar developmental changes were observed during stimulation experiments both in brain slices and in vivo following cochlear ablation. Our data suggest that the strong reduction in release probability and the speedup of the decay of synaptic facilitation that happen just before hearing onset are important events in the transformation of the calyx of Held synapse into an auditory relay synapse.
doi:10.1523/JNEUROSCI.1995-11.2011
PMCID: PMC4314708  PMID: 21832200
12.  SNAP-29-mediated Modulation of Synaptic Transmission in Cultured Hippocampal Neurons* 
The Journal of biological chemistry  2005;280(27):25769-25779.
Identifying the molecules that regulate both the recycling of synaptic vesicles and the SNARE components required for fusion is critical for elucidating the molecular mechanisms underlying synaptic plasticity. SNAP-29 was initially isolated as a syntaxin-binding and ubiquitously expressed protein. Previous studies have suggested that SNAP-29 inhibits SNARE complex disassembly, thereby reducing synaptic transmission in cultured superior cervical ganglion neurons in an activity-dependent manner. However, the role of SNAP-29 in regulating synaptic vesicle recycling and short-term plasticity in the central nervous system remains unclear. In the present study, we examined the effect of SNAP-29 on synaptic transmission in cultured hippocampal neurons by dual patch clamp whole-cell recording, FM dye imaging, and immunocytochemistry. Our results demonstrated that exogenous expression of SNAP-29 in presynaptic neurons significantly decreased the efficiency of synaptic transmission after repetitive firing within a few minutes under low and moderate frequency stimulations (0.1 and 1 Hz). In contrast, SNAP-29 did not affect the density of synapses and basal synaptic transmission. Whereas neurotransmitter release was unaffected during intensive stimulation, recovery after synaptic depression was impaired by SNAP-29. Furthermore, knockdown of SNAP-29 expression in neurons by small interfering RNA increased the efficiency of synaptic transmission during repetitive firing. These findings suggest that SNAP-29 acts as a negative modulator for neurotransmitter release, probably by slowing recycling of the SNARE-based fusion machinery and synaptic vesicle turnover.
doi:10.1074/jbc.M502356200
PMCID: PMC1864940  PMID: 15890653
13.  Short-term synaptic plasticity and intensity coding 
Hearing research  2011;279(1-2):13-21.
Alterations in synaptic strength over short time scales, termed short-term synaptic plasticity, can gate the flow of information through neural circuits. Different information can be extracted from the same presynaptic spike train depending on the activity- and time-dependent properties of the plasticity at a given synapse. The parallel processing in the brain stem auditory pathways provides an excellent model system for investigating the functional implications of short-term plasticity in neural coding. We review recent evidence that short-term plasticity differs in different pathways with a special emphasis on the ‘intensity’ pathway. While short-term depression dominates the ‘timing’ pathway, the intensity pathway is characterized by a balance of short-term depression and facilitation that allows linear transmission of rate-coded intensity information. Target-specific regulation of presynaptic plasticity mechanisms underlies the differential expression of depression and facilitation. The potential contribution of short-term plasticity to different aspects of ‘intensity’-related information processing, such as interaural level/intensity difference coding, amplitude modulation coding, and intensity-dependent gain control coding, is discussed.
doi:10.1016/j.heares.2011.03.001
PMCID: PMC3210195  PMID: 21397676
14.  Difference in response reliability predicted by spectrotemporal tuning in the cochlear nuclei of barn owls 
The brainstem auditory pathway is obligatory for all aural information. Brainstem auditory neurons must encode the level and timing of sounds, as well as their time-dependent spectral properties, the fine structure and envelope, which are essential for sound discrimination. This study focused on envelope coding in the two cochlear nuclei of the barn owl, nucleus angularis (NA) and nucleus magnocellularis (NM). NA and NM receive input from bifurcating auditory nerve fibers and initiate processing pathways specialized in encoding interaural time (ITD) and level (ILD) differences, respectively. We found that NA neurons, though unable to accurately encode stimulus phase, lock more strongly to the stimulus envelope than NM units. The spectrotemporal receptive fields (STRFs) of NA neurons exhibit a pre-excitatory suppressive field. Using multilinear regression analysis and computational modeling, we show that this feature of STRFs can account for enhanced across-trial response reliability, by locking spikes to the stimulus envelope. Our findings indicate a dichotomy in envelope coding between the time and intensity processing pathways as early as at the level of the cochlear nuclei. This allows the ILD processing pathway to encode envelope information with greater fidelity than the ITD processing pathway. Furthermore, we demonstrate that the properties of the neurons’ STRFs can be quantitatively related to spike timing reliability.
doi:10.1523/JNEUROSCI.5422-10.2011
PMCID: PMC3059808  PMID: 21368035
Nucleus angularis; STRF; spectrotemporal tuning; cochlear nuclei; barn owl; response reliability
15.  Transmitter release from cochlear hair cells is phase-locked to cyclic stimuli of different intensities and frequencies 
The auditory system processes time and intensity through separate brainstem pathways to derive spatial location as well as other salient features of sound. The independent coding of time and intensity begins in the cochlea where afferent neurons can fire action potentials at constant phase throughout a wide range of stimulus intensities. We have investigated time and intensity coding by simultaneous pre- and post-synaptic recording at the hair cell-afferent synapse from rats. Trains of depolarizing steps to the hair cell were used to elicit postsynaptic currents that occurred at constant phase, for a range of membrane potentials over which release probability varied significantly. To probe the underlying mechanisms, release was examined using single steps to various command voltages. As expected for vesicular release, first synaptic events occurred earlier as presynaptic calcium influx grew larger. However, synaptic depression produced smaller responses with longer first latencies. Thus, during repetitive hair cell stimulation, as the hair cell is more strongly depolarized, increased calcium channel gating hurries transmitter release, but the resulting vesicular depletion produces a compensatory slowing. Quantitative simulation of ribbon function shows that these two factors varied reciprocally with hair cell depolarization (stimulus intensity) to produce constant synaptic phase. Finally, we propose that the observed rapid vesicle replenishment would help maintain the vesicle pool, which in turn would equilibrate with the stimulus intensity (and therefore, the number of open Ca2+ channels), so for trains of different levels the average phase will be conserved.
doi:10.1523/JNEUROSCI.0457-12.2012
PMCID: PMC3705563  PMID: 23175853
hair cell; ribbon synapse; synaptic; afferent; auditory nerve; exocytosis; phase-locking
16.  The localization and physiological effects of cannabinoid receptor 1 (CB1) in the brain stem auditory system of the chick 
Neuroscience  2011;194C:150-159.
Fast, temporally-precise, and consistent synaptic transmission is required to encode features of acoustic stimuli. Neurons of nucleus magnocellularis (NM) in the auditory brain stem of the chick possess numerous adaptations to optimize the coding of temporal information. One potential problem for the system is the depression of synaptic transmission during a prolonged stimulus. The present studies tested the hypothesis that cannabinoid receptor one (CB1) signaling may limit synaptic depression at the auditory nerve-NM synapse. In situ hybridization was used to confirm that CB1 mRNA is expressed in the cochlear ganglion; immunohistochemistry was used to confirm the presence of CB1 protein in NM. These findings are consistent with the common presynaptic locus of CB1 in the brain. Rate-dependent synaptic depression was then examined in a brain slice preparation before and after administration of WIN 55,212-2 (WIN), a potent CB1 agonist. WIN decreased the amplitude of excitatory postsynaptic currents and also reduced depression across a train of stimuli. The effect was most obvious late in the pulse train and during high rates of stimulation. This CB1-mediated influence could allow for lower, but more consistent activation of NM neurons, which could be of importance for optimizing the coding of prolonged, temporally-locked acoustic stimuli.
doi:10.1016/j.neuroscience.2011.05.061
PMCID: PMC3182287  PMID: 21703331
cochlear nucleus; synaptic depression; nucleus magnocellularis; brain slice; WIN 55,212-2; calyx
17.  Synaptic Zn2+ Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis 
Although it is well established that many glutamatergic neurons sequester Zn2+ within their synaptic vesicles, the physiological significance of synaptic Zn2+ remains poorly understood. In experiments performed in a Zn2+-enriched auditory brainstem nucleus -- the dorsal cochlear nucleus -- we discovered that synaptic Zn2+ and GPR39, a putative metabotropic Zn2+-sensing receptor (mZnR), are necessary for triggering the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). The postsynaptic production of 2-AG, in turn, inhibits presynaptic probability of neurotransmitter release, thus shaping synaptic strength and short-term synaptic plasticity. Zn2+-induced inhibition of transmitter release is absent in mutant mice that lack either vesicular Zn2+ or the mZnR. Moreover, mass spectrometry measurements of 2-AG levels reveal that Zn2+-mediated initiation of 2-AG synthesis is absent in mice lacking the mZnR. We reveal a previously unknown action of synaptic Zn2+: synaptic Zn2+ inhibits glutamate release by promoting 2-AG synthesis.
doi:10.1523/JNEUROSCI.0237-13.2013
PMCID: PMC3733213  PMID: 23719795
18.  Cell-type specific short-term plasticity at auditory nerve synapses controls feed-forward inhibition in the dorsal cochlear nucleus 
Feed-forward inhibition (FFI) represents a powerful mechanism by which control of the timing and fidelity of action potentials in local synaptic circuits of various brain regions is achieved. In the cochlear nucleus, the auditory nerve provides excitation to both principal neurons and inhibitory interneurons. Here, we investigated the synaptic circuit associated with fusiform cells (FCs), principal neurons of the dorsal cochlear nucleus (DCN) that receive excitation from auditory nerve fibers and inhibition from tuberculoventral cells (TVCs) on their basal dendrites in the deep layer of DCN. Despite the importance of these inputs in regulating fusiform cell firing behavior, the mechanisms determining the balance of excitation and FFI in this circuit are not well understood. Therefore, we examined the timing and plasticity of auditory nerve driven FFI onto FCs. We find that in some FCs, excitatory and inhibitory components of FFI had the same stimulation thresholds indicating they could be triggered by activation of the same fibers. In other FCs, excitation and inhibition exhibit different stimulus thresholds, suggesting FCs and TVCs might be activated by different sets of fibers. In addition, we find that during repetitive activation, synapses formed by the auditory nerve onto TVCs and FCs exhibit distinct modes of short-term plasticity. Feed-forward inhibitory post-synaptic currents (IPSCs) in FCs exhibit short-term depression because of prominent synaptic depression at the auditory nerve-TVC synapse. Depression of this feedforward inhibitory input causes a shift in the balance of fusiform cell synaptic input towards greater excitation and suggests that fusiform cell spike output will be enhanced by physiological patterns of auditory nerve activity.
doi:10.3389/fncir.2014.00078
PMCID: PMC4081852  PMID: 25071459
dorsal cochlear nucleus; auditory nerve; synaptic transmission; synaptic plasticity; feedforward inhibition
19.  Theoretical foundations of the sound analog membrane potential that underlies coincidence detection in the barn owl 
A wide variety of neurons encode temporal information via phase-locked spikes. In the avian auditory brainstem, neurons in the cochlear nucleus magnocellularis (NM) send phase-locked synaptic inputs to coincidence detector neurons in the nucleus laminaris (NL) that mediate sound localization. Previous modeling studies suggested that converging phase-locked synaptic inputs may give rise to a periodic oscillation in the membrane potential of their target neuron. Recent physiological recordings in vivo revealed that owl NL neurons changed their spike rates almost linearly with the amplitude of this oscillatory potential. The oscillatory potential was termed the sound analog potential, because of its resemblance to the waveform of the stimulus tone. The amplitude of the sound analog potential recorded in NL varied systematically with the interaural time difference (ITD), which is one of the most important cues for sound localization. In order to investigate the mechanisms underlying ITD computation in the NM-NL circuit, we provide detailed theoretical descriptions of how phase-locked inputs form oscillating membrane potentials. We derive analytical expressions that relate presynaptic, synaptic, and postsynaptic factors to the signal and noise components of the oscillation in both the synaptic conductance and the membrane potential. Numerical simulations demonstrate the validity of the theoretical formulations for the entire frequency ranges tested (1–8 kHz) and potential effects of higher harmonics on NL neurons with low best frequencies (<2 kHz).
doi:10.3389/fncom.2013.00151
PMCID: PMC3821005  PMID: 24265616
phase-locking; sound localization; auditory brainstem; periodic signals; oscillation; owl
20.  Activation of Synaptic Group II Metabotropic Glutamate Receptors Induces Long-Term Depression at GABAergic Synapses in CNS Neurons 
The Journal of Neuroscience  2013;33(40):15964-15977.
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.
doi:10.1523/JNEUROSCI.0202-13.2013
PMCID: PMC3787505  PMID: 24089501
21.  Cholinergic Modulation of Large-Conductance Calcium-Activated Potassium Channels Regulates Synaptic Strength and Spine Calcium in Cartwheel Cells of the Dorsal Cochlear Nucleus 
The Journal of Neuroscience  2014;34(15):5261-5272.
Acetylcholine is a neuromodulatory transmitter that controls synaptic plasticity and sensory processing in many brain regions. The dorsal cochlear nucleus (DCN) is an auditory brainstem nucleus that integrates auditory signals from the cochlea with multisensory inputs from several brainstem nuclei and receives prominent cholinergic projections. In the auditory periphery, cholinergic modulation serves a neuroprotective function, reducing cochlear output under high sound levels. However, the role of cholinergic signaling in the DCN is less understood. Here we examine postsynaptic mechanisms of cholinergic modulation at glutamatergic synapses formed by parallel fiber axons onto cartwheel cells (CWCs) in the apical DCN circuit from mouse brainstem slice using calcium (Ca) imaging combined with two-photon laser glutamate uncaging onto CWC spines. Activation of muscarinic acetylcholine receptors (mAChRs) significantly increased the amplitude of both uncaging-evoked EPSPs (uEPSPs) and spine Ca transients. Our results demonstrate that mAChRs in CWC spines act by suppressing large-conductance calcium-activated potassium (BK) channels, and this effect is mediated through the cAMP/protein kinase A signaling pathway. Blocking BK channels relieves voltage-dependent magnesium block of NMDA receptors, thereby enhancing uEPSPs and spine Ca transients. Finally, we demonstrate that mAChR activation inhibits L-type Ca channels and thus may contribute to the suppression of BK channels by mAChRs. In summary, we demonstrate a novel role for BK channels in regulating glutamatergic transmission and show that this mechanism is under modulatory control of mAChRs.
doi:10.1523/JNEUROSCI.3728-13.2014
PMCID: PMC3983802  PMID: 24719104
22.  Synaptic Plasticity in the Medial Superior Olive of Hearing, Deaf, and Cochlear-Implanted Cats 
The Journal of comparative neurology  2012;520(10):2202-2217.
The medial superior olive (MSO) is a key auditory brain-stem structure that receives binaural inputs and is implicated in processing interaural time disparities used for sound localization. The deaf white cat, a proven model of congenital deafness, was used to examine how deafness and cochlear implantation affected the synaptic organization at this binaural center in the ascending auditory pathway. The patterns of axosomatic and axodendritic organization were determined for principal neurons from the MSO of hearing, deaf, and deaf cats with cochlear implants. The nature of the synapses was evaluated through electron microscopy, ultrastructure analysis of the synaptic vesicles, and immunohistochemistry. The results show that the proportion of inhibitory axosomatic terminals was significantly smaller in deaf animals when compared with hearing animals. However, after a period of electrical stimulation via cochlear implants the proportion of inhibitory inputs resembled that of hearing animals. Additionally, the excitatory axodendritic boutons of hearing cats were found to be significantly larger than those of deaf cats. Boutons of stimulated cats were significantly larger than the boutons in deaf cats, although not as large as in the hearing cats, indicating a partial recovery of excitatory inputs to MSO dendrites after stimulation. These results exemplify dynamic plasticity in the auditory brainstem and reveal that electrical stimulation through cochlear implants has a restorative effect on synaptic organization in the MSO.
doi:10.1002/cne.23038
PMCID: PMC3963361  PMID: 22237661
synaptic excitation and inhibition; synaptic vesicles; congenital deafness; cochlear implant stimulation
23.  Connections of the Auditory Brainstem in a Songbird, Taeniopygia guttata. I. Projections of Nucleus Angularis and Nucleus Laminaris to the Auditory Torus 
The Journal of comparative neurology  2010;518(11):10.1002/cne.22334.
Auditory information is important for social and reproductive behaviors in birds generally, but is crucial for oscine species (songbirds), in particular because in these species auditory feedback ensures the learning and accurate maintenance of song. While there is considerable information on the auditory projections through the forebrain of songbirds, there is no information available for projections through the brainstem. At the latter levels the prevalent model of auditory processing in birds derives from an auditory specialist, the barn owl, which uses time and intensity parameters to compute the location of sounds in space, but whether the auditory brainstem of songbirds is similarly functionally organized is unknown. To examine the songbird auditory brainstem we charted the projections of the cochlear nuclei angularis (NA) and magnocellularis (NM) and the third-order nucleus laminaris (NL) in zebra finches using standard tract-tracing techniques. As in other avian species, the projections of NM were found to be confined to NL, and NL and NA provided the ascending projections. Here we report on differential projections of NA and NL to the torus semicircularis, known in birds as nucleus mesencephalicus lateralis, pars dorsalis (MLd), and in mammals as the central nucleus of the inferior colliculus (ICc). Unlike the case in nonsongbirds, the projections of NA and NL to MLd in the zebra finch showed substantial overlap, in agreement with the projections of the cochlear nuclei to the ICc in mammals. This organization could suggest that the “what” of auditory stimuli is as important as “where.”
doi:10.1002/cne.22334
PMCID: PMC3862038  PMID: 20394061
cochlear nuclei; central nucleus of inferior colliculus; MLd; zebra finch; avian
24.  High Bandwidth Synaptic Communication and Frequency Tracking in Human Neocortex 
PLoS Biology  2014;12(11):e1002007.
Because of fast recovery from synaptic depression and fast-initiated action potentials, neuronal information transfer can have a substantially higher bandwidth in human neocortical circuits than in those of rodents.
Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from connected pairs of pyramidal neurons in acute brain slices of adult human and mouse temporal cortex and probed the dynamical properties of use-dependent plasticity. We found that human synaptic connections were purely depressing and that they recovered three to four times more swiftly from depression than synapses in rodent neocortex. Thereby, during realistic spike trains, the temporal resolution of synaptic information exchange in human synapses substantially surpasses that in mice. Using information theory, we calculate that information transfer between human pyramidal neurons exceeds that of mouse pyramidal neurons by four to nine times, well into the beta and gamma frequency range. In addition, we found that human principal cells tracked fine temporal features, conveyed in received synaptic inputs, at a wider bandwidth than for rodents. Action potential firing probability was reliably phase-locked to input transients up to 1,000 cycles/s because of a steep onset of action potentials in human pyramidal neurons during spike trains, unlike in rodent neurons. Our data show that, in contrast to the widely held views of limited information transfer in rodent depressing synapses, fast recovering synapses of human neurons can actually transfer substantial amounts of information during spike trains. In addition, human pyramidal neurons are equipped to encode high synaptic information content. Thus, adult human cortical microcircuits relay information at a wider bandwidth than rodent microcircuits.
Author Summary
Our ability to think, memorize information, and act appropriately depends on circuits of connected neurons in the brain. In these circuits, neurons pass information to each other using electric pulses (action potentials) that cause the release of chemical neurotransmitters, which alter the membrane electric potential of receiving neurons. Based on the inputs neurons receive, they decide whether to transmit action potentials to other neurons in the circuit to pass on information. During sequences of repeated information transfer, synaptic connections between two neurons temporarily become weaker by synaptic depression. Our knowledge of neuronal information transfer is based on rodent neurons. The properties of synaptic information transfer and synaptic depression in humans are not known. Here, we show that adult human neurons can transfer information with up to ten times higher rates than mouse neurons, because of a three to four times faster recovery from depression. Furthermore, we found that human neurons can respond faster to synaptic inputs, owing to faster initiation of action potentials. Human neurons can thereby reliably encode high input frequencies in their output. Thus, neuronal information transfer can have a substantially higher bandwidth in human neocortical circuits than in rodent brains.
doi:10.1371/journal.pbio.1002007
PMCID: PMC4244038  PMID: 25422947
25.  Glycinergic transmission modulates GABAergic inhibition in the avian auditory pathway 
For all neurons, a proper balance of synaptic excitation and inhibition is crucial to effect computational precision. Achievement of this balance is remarkable when one considers factors that modulate synaptic strength operate on multiple overlapping time scales and affect both pre- and postsynaptic elements. Recent studies have shown that inhibitory transmitters, glycine and GABA, are co-released in auditory nuclei involved in the computation of interaural time disparities (ITDs), a cue used to process sound source location. The co-release expressed at these synapses is heavily activity dependent, and generally occurs when input rates are high. This circuitry, in both birds and mammals, relies on inhibitory input to maintain the temporal precision necessary for ITD encoding. Studies of co-release in other brain regions suggest that GABA and glycine receptors (GlyRs) interact via cross-suppressive modulation of receptor conductance. We performed in vitro whole-cell recordings in several nuclei of the chicken brainstem auditory circuit to assess whether this cross-suppressive phenomenon was evident in the avian brainstem. We evaluated the effect of pressure-puff applied glycine on synaptically evoked inhibitory currents in nucleus magnocellularis (NM) and the superior olivary nucleus (SON). Glycine pre-application reduced the amplitude of inhibitory postsynaptic currents (IPSCs) evoked during a 100 Hz train stimulus in both nuclei. This apparent glycinergic modulation was blocked in the presence of strychnine. Further experiments showed that this modulation did not depend on postsynaptic biochemical interactions such as phosphatase activity, or direct interactions between GABA and GlyR proteins. Rather, voltage clamp experiments in which we manipulated Cl− flux during agonist application suggest that activation of one receptor will modulate the conductance of the other via local changes in Cl− ion concentration within microdomains of the postsynaptic membrane.
doi:10.3389/fncir.2014.00019
PMCID: PMC3954080  PMID: 24672432
glycine; GABA; inhibition; cross-suppression; interaural time disparities

Results 1-25 (1007449)