Assessment of Possible Contributions of Hyaluronan and Proteoglycan Binding Link Protein 4 to Differential Perineuronal Net Formation at the Calyx of Held

The calyx of Held is a giant nerve terminal mediating high-frequency excitatory input to principal cells of the medial nucleus of the trapezoid body (MNTB). MNTB principal neurons are enwrapped by densely organized extracellular matrix structures, known as perineuronal nets (PNNs). Emerging evidence indicates the importance of PNNs in synaptic transmission at the calyx of Held. Previously, a unique differential expression of aggrecan and brevican has been reported at this calyceal synapse. However, the role of hyaluronan and proteoglycan binding link proteins (HAPLNs) in PNN formation and synaptic transmission at this synapse remains elusive. This study aimed to assess immunohistochemical evidence for the effect of HAPLN4 on differential PNN formation at the calyx of Held. Genetic deletion of Hapln4 exhibited a clear ectopic shift of brevican localization from the perisynaptic space between the calyx of Held terminals and principal neurons to the neuropil surrounding the whole calyx of Held terminals. In contrast, aggrecan expression showed a consistent localization at the surrounding neuropil, together with HAPLN1 and tenascin-R, in both gene knockout (KO) and wild-type (WT) mice. An in situ proximity ligation assay demonstrated the molecular association of brevican with HAPLN4 in WT and HAPLN1 in gene KO mice. Further elucidation of the roles of HAPLN4 may highlight the developmental and physiological importance of PNN formation in the calyx of Held.

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Presynaptic CaV2.1 calcium channels carrying familial hemiplegic migraine mutation R192Q allow faster recovery from synaptic depression in mouse calyx of Held

Journal of Neurophysiology ◽

10.1152/jn.01183.2011 ◽

2012 ◽

Vol 108 (11) ◽

pp. 2967-2976 ◽

Cited By ~ 15

Author(s):

Carlota González Inchauspe ◽

Francisco J. Urbano ◽

Mariano N. Di Guilmi ◽

Michel D. Ferrari ◽

Arn M. J. M. van den Maagdenberg ◽

...

Keyword(s):

Synaptic Transmission ◽

Close Association ◽

Low Frequency ◽

Familial Hemiplegic Migraine ◽

Missense Mutations ◽

Calyx Of Held ◽

Hemiplegic Migraine ◽

Calcium Sensors ◽

Medial Nucleus ◽

Key Factor

CaV2.1 Ca2+ channels have a dominant and specific role in initiating fast synaptic transmission at central excitatory synapses, through a close association between release sites and calcium sensors. Familial hemiplegic migraine type 1 (FHM-1) is an autosomal-dominant subtype of migraine with aura, caused by missense mutations in the CACNA1A gene that encodes the α1A pore-forming subunit of CaV2.1 channel. We used knock-in (KI) transgenic mice harboring the FHM-1 mutation R192Q to study the consequences of this mutation in neurotransmission at the giant synapse of the auditory system formed by the presynaptic calyx of Held terminal and the postsynaptic neurons of the medial nucleus of the trapezoid body (MNTB). Although synaptic transmission seems unaffected by low-frequency stimulation in physiological Ca2+ concentration, we observed that with low Ca2+ concentrations (<1 mM) excitatory postsynaptic currents (EPSCs) showed increased amplitudes in R192Q KI mice compared with wild type (WT), meaning significant differences in the nonlinear calcium dependence of nerve-evoked transmitter release. In addition, when EPSCs were evoked by broadened presynaptic action potentials (achieved by inhibition of K+ channels) via Cav2.1-triggered exocytosis, R192Q KI mice exhibited further enhancement of EPSC amplitude and charge compared with WT mice. Repetitive stimulation of afferent axons to the MNTB at different frequencies caused short-term depression of EPSCs that recovered significantly faster in R192Q KI mice than in WT mice. Faster recovery in R192Q KI mice was prevented by the calcium chelator EGTA-AM, pointing to enlarged residual calcium as a key factor in accelerating the replenishment of synaptic vesicles.

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Endogenous Activation of Adenosine A1 Receptors, but Not P2X Receptors, During High-Frequency Synaptic Transmission at the Calyx of Held

Journal of Neurophysiology ◽

10.1152/jn.00694.2005 ◽

2006 ◽

Vol 95 (6) ◽

pp. 3336-3342 ◽

Cited By ~ 24

Author(s):

Adrian Y. C. Wong ◽

Brian Billups ◽

Jamie Johnston ◽

Richard J. Evans ◽

Ian D. Forsythe

Keyword(s):

Synaptic Transmission ◽

High Frequency ◽

Atp Release ◽

Physiological Role ◽

P2x Receptors ◽

Presynaptic Receptors ◽

Calyx Of Held ◽

Adenosine A1 Receptors ◽

Medial Nucleus ◽

Adenosine A1

Activation of presynaptic receptors plays an important role in modulation of transmission at many synapses, particularly during high-frequency trains of stimulation. Adenosine-triphosphate (ATP) is coreleased with several neurotransmitters and acts at presynaptic sites to reduce transmitter release; such presynaptic P2X receptors occur at inhibitory and excitatory terminals in the medial nucleus of the trapezoid body (MNTB). We have investigated the mechanism of purinergic modulation during high-frequency repetitive stimulation at the calyx of Held synapse. Suppression of calyceal excitatory postsynaptic currents (EPSCs) by ATP and ATPγS (100 μM) was mimicked by adenosine application and was blocked by DPCPX (10 μM), indicating mediation by adenosine A1 receptors. DPCPX enhanced EPSC amplitudes during high-frequency synaptic stimulation, suggesting that adenosine has a physiological role in modulating transmission at the calyx. The Luciferin-Luciferase method was used to probe for endogenous ATP release (at 37°C), but no release was detected. Blockers of ectonucleotidases also had no effect on endogenous synaptic depression, suggesting that it is adenosine acting on A1 receptors, rather than degradation of released ATP, which accounts for presynaptic purinergic suppression of synaptic transmission during physiological stimulus trains at this glutamatergic synapse.

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Multiple Large Inputs to Principal Cells in the Mouse Medial Nucleus of the Trapezoid Body

Journal of Neurophysiology ◽

10.1152/jn.00927.2003 ◽

2004 ◽

Vol 92 (1) ◽

pp. 545-552 ◽

Cited By ~ 19

Author(s):

Jeremy B. Bergsman ◽

Pietro De Camilli ◽

David A. McCormick

Keyword(s):

Sound Localization ◽

Excitatory Input ◽

Nerve Terminals ◽

Calyx Of Held ◽

Anatomical Studies ◽

Principal Cells ◽

Medial Nucleus ◽

Central Synapse ◽

Auditory Brain Stem ◽

Trapezoid Body

The calyx of Held is a giant nerve terminal that forms a synapse directly onto the principal cells of the medial nucleus of the trapezoid body (MNTB) in the mammalian auditory brain stem. This central synapse, which is involved in sound localization, has become widely used for studying synaptic transmission. Anatomical studies of this nucleus have indicated that each principal cell is innervated by only one calyx. Here we use previously established electrophysiological criteria of excitatory postsynaptic current amplitude, kinetics, and transmitter type, as well as other characteristics commonly reported for this synapse, to examine the input properties of principal neurons. Our findings indicate that some principal cells receive more than one strong excitatory input. These inputs meet previously established electrophysiological criteria for identification as calyceal nerve terminals. Implications for the execution and analysis of experiments to avoid errors due to such multiple inputs are discussed.

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Faculty Opinions recommendation of Vesicular Glutamate Transporter Expression Ensures High-Fidelity Synaptic Transmission at the Calyx of Held Synapses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738522462.793577970 ◽

2020 ◽

Author(s):

Ege Kavalali

Keyword(s):

Synaptic Transmission ◽

Glutamate Transporter ◽

High Fidelity ◽

Vesicular Glutamate Transporter ◽

Calyx Of Held ◽

Transporter Expression

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Perinatal Development of the Medial Nucleus of the Trapezoid Body

The Oxford Handbook of the Auditory Brainstem ◽

10.1093/oxfordhb/9780190849061.013.22 ◽

2018 ◽

pp. 244-272

Author(s):

Shobhana Sivaramakrishnan ◽

Ashley Brandebura ◽

Paul Holcomb ◽

Daniel Heller ◽

Douglas Kolson ◽

...

Keyword(s):

Axon Guidance ◽

Neural Circuit ◽

Neural Cells ◽

Calyx Of Held ◽

Medial Nucleus ◽

Target Neuron ◽

Circuit Formation ◽

Key Events ◽

The Brain ◽

Trapezoid Body

Bushy cells (BC) of the cochlear nucleus mono-innervate their target neuron, the principal cell of the medial nucleus of the trapezoid body (MNTB), via the calyx of Held (CH) terminal, which is a typically mammalian structure and perhaps the largest nerve terminal in the brain. CH:MNTB innervation has become an attractive model to study neural circuit formation because it forms quickly, passing through stages of competition in mice within 2–4 days. BCs innervate MNTB neurons by E17, but CHs do not begin to grow for another five days (P3). Progress has been made to identify molecular factors for axon guidance, CH growth, and physiological maturation of synaptic partners, but important details remain to be discovered. We summarize key events in CH formation and highlight unresolved issues in molecular and physiological signaling, roles for non-neural cells, and the nature of competition during the first postnatal week.

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Dynamics of sensory afferent synaptic transmission in aortic baroreceptor regions on nucleus tractus solitarius

Journal of Neurophysiology ◽

10.1152/jn.1995.74.4.1518 ◽

1995 ◽

Vol 74 (4) ◽

pp. 1518-1528 ◽

Cited By ~ 49

Author(s):

M. C. Andresen ◽

M. Yang

Keyword(s):

Action Potential ◽

Synaptic Transmission ◽

Frequency Response ◽

Action Potentials ◽

Nucleus Tractus Solitarius ◽

Reversal Potential ◽

Constant Frequency ◽

Epsp Amplitude ◽

Postsynaptic Potentials ◽

Medial Nucleus

1. Synaptic responses of medial nucleus tractus solitarius (mNTS) neurons to solitary tract (ST) activation were studied in a horizontal brain slice preparation of the rat medulla. Slices included sections of ST sufficiently long that the ST could be electrically activated several millimeters from the recording site of cell bodies in mNTS. 2. Three types of synaptic events were evoked in response to ST stimulation: simple excitatory postsynaptic potentials (EPSPs), simple inhibitory postsynaptic potentials (IPSPs), and complex EPSP-IPSP sequences. Simple EPSPs had substantially shorter latencies than IPSPs (3.39 +/- 0.65 ms, mean +/- SE, n = 42, vs. 5.86 +/- 0.71 ms, n = 6, respectively). 3. EPSP amplitude increased linearly with increasing hyperpolarization, with an extrapolated reversal potential near 0 mV. 4. EPSPs were maximal at < 0.5 Hz of sustained, constant-frequency ST stimulation (n = 14). EPSP amplitude declined to an average of 57.5% of control at 10 Hz after 2 s of sustained stimulation. With 1 min of sustained, 100-Hz stimulation, EPSP amplitude declined to near zero. 5. With stimuli intermittently delivered as 100-ms bursts every 300 ms, generally comparable average EPSPs were evoked during constant and burst patterns of ST stimulation. The amplitude of the initial EPSP in each burst was very well maintained even at intraburst stimulation rates of 100 Hz. 6. At resting membrane potentials, low constant frequencies of ST stimulation (< 5 Hz) reliably elicited action potentials and suppressed spontaneous spiking, but higher frequencies led to spike failures (> 85% at 100 Hz). Between 5 and 10 Hz, this periodic stimulation-suppression cycle clearly entrained action potential activity to the ST stimuli. Similar patterns of current pulses (5 ms) reliably evoked action potentials with each pulse to higher frequencies (50 Hz) without failures, and entrainment was similar to ST stimulation. 7. In a subset of nucleus tractus solitarius (NTS) neurons (3 of 9 studied), bursts of ST stimuli were as much as 50% more effective at transmitting high frequencies (> 10 Hz) of ST stimulation than the equivalent constant frequencies (P < 0.0001). 8. The long-latency simple IPSPs with no preceding EPSPs reversed to become depolarizing at potentials more negative than -62.9 +/- 7.0 mV (n = 5) and were blocked by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (n = 3). The ST stimulation frequency-response relation of these IPSPs was similar to that for the short-latency EPSP response excited by ST synapses. Thus these IPSPs appear to be activated polysynaptically via a glutamatergic-GABAergic sequence in response to ST activation. 9. The results suggest that sensory afferent synapses in mNTS have limited transmission of high-frequency inputs. Both synaptic transmission and the characteristics of the postsynaptic neuron importantly contribute to the action potential transmission from afferent to NTS neuron and beyond. This overall frequency response limitation may contribute to the accommodation of reflex responses from sensory afferent inputs such as arterial baroreceptors within their physiological discharge frequency range.

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