Silent Synapses in Developing Cerebellar Granule Neurons

2002 ◽  
Vol 87 (3) ◽  
pp. 1263-1270 ◽  
Author(s):  
Gabriele Losi ◽  
Kate Prybylowski ◽  
ZhanYan Fu ◽  
Jian Hong Luo ◽  
Stefano Vicini
Keyword(s):  
Ampa Receptors ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Glutamate Release ◽  
Long Term Potentiation ◽  
Patch Clamp Technique ◽  
Physiological Concentration ◽  
Cerebellar Granule ◽  
Silent Synapses ◽  
Term Potentiation

Silent synapses are excitatory synapses endowed exclusively with N-methyl-d-aspartate (NMDA) responses that have been proposed to acquire α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses during development and after long-term potentiation (LTP). These synapses are functionally silent because of the Mg2+ block of NMDA receptors at resting potentials. Here we provide evidence for the presence of silent synapses in developing cerebellar granule cells. Using the patch-clamp technique in the whole-cell configuration, we recorded the spontaneous excitatory postsynaptic currents (sEPSCs) from rat cerebellar granule cells in culture and in slices at physiological concentration of Mg2+ (1 mM). A holding potential of +60 mV removes Mg2+ block of NMDA channels, allowing us to record NMDA-sEPSCs. We thus compared the frequency of AMPA-sEPSCs, recorded at −60 mV, with that of NMDA-sEPSCs, recorded at +60 mV. NMDA-sEPSCs occurred at higher frequency than the AMPA-sEPSCs in most cells recorded in slices from rats at postnatal day (P) <13 and in culture at 6–8 days after plating (DIV6–8). In a few cells from young rats (P6–9) and in most neurons in culture at DIV6 we recorded exclusively NMDA-sEPSCs, supporting the hypothesis of existence of functional synapses with NMDA and without AMPA receptors. Increasing glutamate release in the slice with cyclothiazide and temperature increased AMPA and NMDA-sEPSCs frequencies but failed to alter the relative ratio of frequency of occurrence. Frequency ratio of NMDA versus AMPA-sEPSCs in slices was correlated with the weighted time constant of decay (τ w ) of NMDA-sEPSCs and decreased with development along the reported decrease of τ w . We suggest that the prevalence of synaptic NR2A subunits that confer faster kinetics is paralleled by the disappearance of silent synapses early in cerebellar development.

scholarly journals Silent synapses: what are they telling us about long-term potentiation?

2003 ◽  
Vol 358 (1432) ◽  
pp. 727-733 ◽  
Author(s):  
Dimitri M. Kullmann
Keyword(s):  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Glutamate Release ◽  
Postsynaptic Density ◽  
Long Term Potentiation ◽  
Silent Synapses ◽  
Term Potentiation ◽  
Silent Synapse ◽  
Cortical Synapses

At several cortical synapses glutamate release events can be mediated exclusively by NMDA receptors, with no detectable contribution from AMPA receptors. This observation was originally made by comparing the trial-to-trial variability of the two components of synaptic signals evoked in hippocampal neurons, and was subsequently confirmed by recording apparently pure NMDA receptor-mediated EPSCs with stimulation of small numbers of axons. It has come to be known as the ‘silent synapse’ phenomenon, and is widely assumed to be caused by the absence of functional AMPA receptors, which can, however, be recruited into the postsynaptic density by long-term potentiation (LTP) induction. Thus, it provides an important impetus for relating AMPA receptor trafficking mechanisms to the expression of LTP, a theme that is taken up elsewhere in this issue. This article draws attention to several findings that call for caution in identifying silent synapses exclusively with synapses without AMPA receptors. In addition, it attempts to identify several missing pieces of evidence that are required to show that unsilencing of such synapses is entirely accounted for by insertion of AMPA receptors into the postsynaptic density. Some aspects of the early stages of LTP expression remain open to alternative explanations.

scholarly journals Expression mechanisms underlying long-term potentiation: a postsynaptic view

2003 ◽  
Vol 358 (1432) ◽  
pp. 721-726 ◽  
Author(s):  
Roger A. Nicoll
Keyword(s):  
Nmda Receptor ◽  
Ampa Receptors ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Covalent Modification ◽  
Term Potentiation ◽  
Expression Mechanism

This review summarizes the various experiments that have been carried out to determine if the expression of long-term potentiation (LTP), in particular N -methyl-D-aspartate (NMDA) receptor-dependent LTP, is presynaptic or postsynaptic. Evidence for a presynaptic expression mechanism comes primarily from experiments reporting that glutamate overflow is increased during LTP and from experiments showing that the failure rate decreases during LTP. However, other experimental approaches, such as monitoring synaptic glutamate release by recording astrocytic glutamate transporter currents, have failed to detect any change in glutamate release during LTP. In addition, the discovery of silent synapses, in which LTP rapidly switches on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function at NMDA-receptor-only synapses, provides a postsynaptic mechanism for the decrease in failures during LTP. It is argued that the preponderance of evidence favours a postsynaptic expression mechanism, whereby NMDA receptor activation results in the rapid recruitment of AMPA receptors as well as a covalent modification of synaptic AMPA receptors.

Quantifying the Magnitude of Changes in Synaptic Level Parameters With Long-Term Potentiation

2006 ◽  
Vol 96 (3) ◽  
pp. 1478-1491 ◽  
Author(s):  
William R. Holmes ◽  
Lawrence M. Grover
Keyword(s):  
Ampa Receptors ◽  
Single Channel ◽  
Long Term Potentiation ◽  
Channel Conductance ◽  
Single Channel Conductance ◽  
Vesicle Release ◽  
Silent Synapses ◽  
Term Potentiation ◽  
Synaptic Level

Experimental evidence supports a number of mechanisms for the synaptic change that occurs with long-term potentiation (LTP) including insertion of AMPA receptors, an increase in AMPA receptor single channel conductance, unmasking silent synapses, and increases in vesicle release probability. Here we combine experimental and modeling studies to quantify the magnitude of the change needed at the synaptic level to explain LTP with these proposed mechanisms. Whole cell patch recordings were used to measure excitatory postsynaptic potential (EPSP) amplitude in response to near minimal afferent stimulation before and after LTP induction in CA1 pyramidal cells. Detailed neuron and synapse level models were constructed to estimate quantitatively the changes needed to explain the experimental results. For cells in normal artificial cerebrospinal fluid (ACSF), we found a 60% average increase in EPSP amplitude with LTP. This was explained in the models by a 63% increase in the number of activated synapses, a 64% increase in the AMPA receptor single channel conductance, or a 73% increase in the number of AMPA receptors per potentiated synapse. When the percentage LTP was above the average, the required increases through the proposed mechanisms became nonlinear, particularly for increases in the number of receptors. Given constraints from other experimental studies, our quantification suggests that neither unmasking silent synapses nor increasing the numbers of AMPA receptors at synapses is sufficient to explain the magnitude of LTP we observed, but increasing AMPA single channel conductance or vesicle release probability can be sufficient. Our results are most compatible with a combination of mechanisms producing LTP.

AMPA receptors in cerebellar granule cells during development in culture

1995 ◽  
Vol 87 (1) ◽  
pp. 55-61 ◽  
Author(s):  
Nicola J. Hack ◽  
Arja A. Sluiter ◽  
Robert Balázs
Keyword(s):  
Ampa Receptors ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Cerebellar Granule

AMPA Receptors Are Modulated by Tachykinins in Rat Cerebellum Neurons

2005 ◽  
Vol 94 (4) ◽  
pp. 2484-2490 ◽  
Author(s):  
Massimo Pieri ◽  
Cinzia Severini ◽  
Giuseppina Amadoro ◽  
Irene Carunchio ◽  
Christian Barbato ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Direct Action ◽  
Ionic Current ◽  
Pcr Amplification ◽  
Significant Enhancement ◽  
Neurokinin A ◽  
Cerebellar Granule ◽  
Excitatory Action

The peptides of the tachykinin family are widely distributed within the mammalian peripheral and central nervous systems and play a well-recognized role as neuromodulators, although their direct action on cerebellum granule cells have not yet been demonstrated. We have examined the effect of the best known members of the family, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors from rat cerebellar granule cells in culture to assess the ability of these peptides to regulate the glutamatergic input. Both NKA and NKB, but not SP, produce a significant enhancement of ionic current through AMPA receptors activated by the agonist kainate in 53.5 and 46% of patched neurons, respectively. This effect was not observable in the presence of MEN 10,627 and Trp7βAla8, NKA and NKB competitive antagonist receptors, respectively, indicating that the current modulations were mediated by the respective receptors. NKB also produces a significant enhancement of ionic current through the AMPA receptors activated directly by its agonist AMPA and cyclothiazide, an allosteric modulator that selectively suppresses desensitization of AMPA receptors. The presence of NK3 receptors was demonstrated in these neurons by RT-PCR amplification of total RNA extracted from cerebellar granule cells, using NK3-specific primer pairs. Immunocytochemistry experiments, using a specific polyclonal antibody directed against NK3, also confirmed the presence of NK3 receptors and their co-localization with the GLUR2 AMPA subunit in about 54% of cerebellar granule neurons. This study adds the tachykinins to the list of neuromodulators capable of exerting a excitatory action on cerebellar granule cells.

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