Involvement of AMPA receptor desensitization in short‐term synaptic depression at the calyx of Held in developing rats

Koike-Tani, Maki; Kanda, Takeshi; Saitoh, Naoto; Yamashita, Takayuki; Takahashi, Tomoyuki

doi:10.1113/jphysiol.2007.142547

Cited by 46 publications

(70 citation statements)

References 58 publications

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“…The low Pr is compensated for with a high number of release sites (Taschenberger et al, 2002) along with the preferential location of the synapses at the soma, which would cause enough current input for inducing high-fidelity spiking. In addition, from the onset of hearing, the postsynaptic medial nucleus of the trapezoid body cell is equipped with AMPARs that can rapidly recover from desensitization (Koike-Tani et al, 2008). Another example of a cell innervated by a strong excitatory input is the climbing fiberto-Purkinje cell synapse.…”

Section: Discussionmentioning

confidence: 99%

“…Another broad contact area with multiple release sites is found at the calyx of Held synapse, which is also considered as a "relay" of auditory signals (Taschenberger et al, 2002). However, this synapse can maintain high-fidelity signal transfer close to the kilohertz range because of the low release probability (Pr) at individual active zones, which prevents transmitter accumulation in the synaptic cleft and vesicle depletion (Iwasaki and Takahashi, 2001), and because of the presence of postsynaptic AMPARs that quickly recover from desensitization (Joshi et al, 2004;Koike-Tani et al, 2008). But the RG synapses lacked both of these features, and profound paired-pulse depression was attained.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms Underlying Signal Filtering at a Multisynapse Contact

Budisantoso¹,

Matsui²,

Kamasawa³

et al. 2012

J. Neurosci.

111

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Visual information must be relayed through the lateral geniculate nucleus before it reaches the visual cortex. However, not all spikes created in the retina lead to postsynaptic spikes and properties of the retinogeniculate synapse contribute to this filtering. To understand the mechanisms underlying this filtering process, we conducted electrophysiology to assess the properties of signal transmission in the Long-Evans rat. We also performed SDS-digested freeze-fracture replica labeling to quantify the receptor and transporter distribution, as well as EM reconstruction to describe the 3D structure. To analyze the impact of transmitter diffusion on the activity of the receptors, simulations were integrated. We identified that a large contributor to the filtering is the marked paired-pulse depression at this synapse, which was intensified by the morphological characteristics of the contacts. The broad presynaptic and postsynaptic contact area restricts transmitter diffusion two dimensionally. Additionally, the presence of multiple closely arranged release sites invites intersynaptic spillover, which causes desensitization of AMPA receptors. The presence of AMPA receptors that slowly recover from desensitization along with the high presynaptic release probability and multivesicular release at each synapse also contribute to the depression. These features contrast with many other synapses where spatiotemporal spread of transmitter is limited by rapid transmitter clearance allowing synapses to operate more independently. We propose that the micrometer-order structure can ultimately affect the visual information processing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying Signal Filtering at a Multisynapse Contact

Budisantoso¹,

Matsui²,

Kamasawa³

et al. 2012

J. Neurosci.

111

View full text Add to dashboard Cite

show abstract

“…This is not generally observed because several synapses show an early role of desensitization in plasticity that decreases as synapses mature. For example, at the calyx of Held, several studies have documented a contribution of desensitization to depression in young but not mature animals (Joshi and Wang 2002;Koike-Tani et al 2008;Renden et al 2005;Scheuss et al 2002;Taschenberger et al 2002Taschenberger et al , 2005Wong et al 2003). It is not clear what factor is critical for this decrease at the calyx nor why the endbulb differs.…”

Section: Desensitization and Maturationmentioning

confidence: 99%

A Low-Affinity Antagonist Reveals Saturation and Desensitization in Mature Synapses in the Auditory Brain Stem

Chanda

Xu‐Friedman

2010

Journal of Neurophysiology

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Chanda S, Xu-Friedman MA. A low-affinity antagonist reveals saturation and desensitization in mature synapses in the auditory brain stem. J Neurophysiol 103: 1915-1926, 2010. First published January 27, 2010 doi:10.1152/jn.00751.2009. Postsynaptic receptor desensitization has been observed to contribute to depression in immature synapses. However, it is not clear whether desensitization persists and causes depression in mature synapses. We investigate this issue at the endbulb of Held, the synapse made by auditory nerve (AN) fibers onto bushy cells (BCs) of the anteroventral cochlear nucleus, where depression could influence the processing of sound information. Experiments using cyclothiazide (CTZ) have implicated desensitization in endbulbs from postnatal day 16 (P16) to P21 mice, but application of ␥-D-glutamylglycine (DGG) did not reveal desensitization in endbulbs ϾP22. To reconcile these findings, we have studied the effects of both CTZ and DGG on endbulbs from P5 to P40 CBA/CaJ mice. In paired-pulse protocols, both CTZ and DGG reduced depression in all ages at intervals Ͻ10 ms, consistent with their effects preventing desensitization. However, DGG increased depression at intervals Ͼ20 ms, consistent with DGG's use to prevent saturation. DGG application revealed receptor saturation even under conditions of very low release probability. Preventing desensitization by CTZ occluded the effects of DGG on desensitization and revealed the effects of saturation at short intervals. We developed an approach to separate DGG's effect on saturation from its effect on desensitization, which showed that desensitization has an impact during bursts of auditory nerve activity. Dynamic-clamp experiments indicated that desensitization can reduce BC spike probability and increase latency and jitter. Thus desensitization may affect sound processing in the mature auditory system.

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“…Repetitive sequential presynaptic activity at several synapses results in desensitization of postsynaptic AMPA receptors and contributes to short-term plasticity (4,21,5,7). In hippocampal synapses prior work has demonstrated either a clear effect (22), or little evidence for postsynaptic desensitization during paired presynaptic stimuli (10).…”

Section: Paired Pulse Facilitation Is Enhanced In Glua2mentioning

confidence: 99%

AMPA receptor desensitization mutation results in severe developmental phenotypes and early postnatal lethality

Christie

Russell

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate) receptors desensitize rapidly and completely in the continued presence of their endogenous ligand glutamate; however, it is not clear what role AMPA receptor desensitization plays in the brain. We generated a knock-in mouse in which a single amino acid residue, which controls desensitization, was mutated in the GluA2 (GluR2) receptor subunit (GluA2 L483Y ). This mutation was homozygous lethal. However, mice carrying a single mutated allele, GluA2 L483Y/wt , survived past birth, but displayed severe and progressive neurological deficits including seizures and, ultimately, increased mortality. The expression of the AMPA receptor subunits GluA1 and GluA2 was decreased, whereas NMDA receptor protein expression was increased in GluA2 L483Y/wt mice. Despite this, basal synaptic transmission and plasticity in the hippocampus were largely unaffected, suggesting that neurons preferentially target receptors to synapses to normalize synaptic weight. We found no gross neuroanatomical alterations in GluA2 L483Y/wt mice. Moreover, there was no accumulation of AMPA receptor subunits in intracellular compartments, suggesting that folding and assembly of AMPA receptors are not affected by this mutation. Interestingly, EPSC paired pulse ratios in the CA1 were enhanced without a change in synaptic release probability, demonstrating that postsynaptic receptor properties can contribute to facilitation. The dramatic phenotype observed in this study by the introduction of a single amino acid change demonstrates an essential role in vivo for AMPA receptor desensitization.MPA receptors are tetramers assembled from the four receptor subunits GluA1-GluA4 (GluR1-4) (1). These receptors are activated by their endogenous ligand glutamate, and rapidly undergo desensitization within milliseconds of glutamate binding. Desensitization involves a conformational change of the receptor complex that allows closure of the channel gate while glutamate remains bound to the receptor (2). Synaptic currents are predominantly mediated by AMPA receptors at most excitatory synapses; therefore there has been interest in the development of pharmacological agents that enhance AMPA receptor function by limiting receptor deactivation and desensitization (3). There are many clear examples of synapses at which postsynaptic receptor desensitization plays a major role in synaptic depression (4-6). Many of these synapses are specialized structures in which glutamate remains in the synaptic cleft for prolonged periods of time during normal operation of the synapse (7). In contrast, at synapses where cleft glutamate is cleared rapidly or where AMPA receptor stoichiometry has become specialized to support high frequency transmission, there is little evidence that synaptic receptor desensitization has much influence on shaping the kinetics of transmission, and it is likely that receptor deactivation is the primary determinant of EPSC time-course (8-10).To determine the importance of AMPA receptor desensitizatio...

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Involvement of AMPA receptor desensitization in short‐term synaptic depression at the calyx of Held in developing rats

Cited by 46 publications

References 58 publications

Mechanisms Underlying Signal Filtering at a Multisynapse Contact

Mechanisms Underlying Signal Filtering at a Multisynapse Contact

A Low-Affinity Antagonist Reveals Saturation and Desensitization in Mature Synapses in the Auditory Brain Stem

AMPA receptor desensitization mutation results in severe developmental phenotypes and early postnatal lethality

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