PRESYNAPTIC MECHANISMS UNDERLYING THE MAINTENANCE OF LONG-TERM POTENTIATION IN THE HIPPOCAMPUS

Long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus has been investigated in great detail over the past 40 years. Where and how LTP is actually expressed, however, remain controversial issues. Considerable evidence has been offered to support both pre- and postsynaptic contributions to LTP expression. Though it is widely held that postsynaptic expression mechanisms are the primary contributors to LTP expression, evidence for that conclusion is amenable to alternative explanations. Here, we briefly review some key contributions to the ‘locus’ debate and describe data that support a dominant role for presynaptic mechanisms. Recognition of the state-dependency of expression mechanisms, and consideration of the consequences of the spatial relationship between postsynaptic glutamate receptors and presynaptic vesicular release sites, lead to a model that may reconcile views from both sides of the synapse.

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Fusion pore modulation as a presynaptic mechanism contributing to expression of long-term potentiation

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2002.1249 ◽

2003 ◽

Vol 358 (1432) ◽

pp. 695-705 ◽

Cited By ~ 58

Author(s):

Sukwoo Choi ◽

Jürgen Klingauf ◽

Richard W. Tsien

Keyword(s):

Nmda Receptor ◽

Glutamate Release ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Quantitative Model ◽

Fusion Pore ◽

Silent Synapses ◽

Term Potentiation ◽

Presynaptic Mechanisms

Working on the idea that postsynaptic and presynaptic mechanisms of long-term potentiation (LTP) expression are not inherently mutually exclusive, we have looked for the existence and functionality of presynaptic mechanisms for augmenting transmitter release in hippocampal slices. Specifically, we asked if changes in glutamate release might contribute to the conversion of ‘silent synapses’ that show N -methyl-D-aspartate (NMDA) responses but no detectable α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses, to ones that exhibit both. Here, we review experiments where NMDA receptor responses provided a bioassay of cleft glutamate concentration, using opposition between peak [glu] cleft and a rapidly reversible antagonist, L-AP5. We discuss findings of a dramatic increase in peak [glu] cleft upon expression of pairing-induced LTP (Choi). We present simulations with a quantitative model of glutamatergic synaptic transmission that includes modulation of the presynaptic fusion pore, realistic cleft geometry and a distributed array of postsynaptic receptors and glutamate transporters. The modelling supports the idea that changes in the dynamics of glutamate release can contribute to synaptic unsilencing. We review direct evidence from Renger et al ., in accord with the modelling, that trading off the strength and duration of the glutamate transient can markedly alter AMPA receptor responses with little effect on NMDA receptor responses. An array of additional findings relevant to fusion pore modulation and its proposed contribution to LTP expression are considered.

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Presynaptic Mechanisms in Hippocampal Long-term Potentiation

Cold Spring Harbor Symposia on Quantitative Biology ◽

10.1101/sqb.1990.055.01.015 ◽

1990 ◽

Vol 55 (0) ◽

pp. 119-129 ◽

Cited By ~ 17

Author(s):

T.V.P. Bliss ◽

M.L. Errington ◽

M.A. Lynch ◽

J.H. Williams

Keyword(s):

Long Term Potentiation ◽

Term Potentiation ◽

Presynaptic Mechanisms

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Role of Platelet-Activating Factor in Long-Term Potentiation of the Rat Medial Vestibular Nuclei

Journal of Neurophysiology ◽

10.1152/jn.1998.79.6.3266 ◽

1998 ◽

Vol 79 (6) ◽

pp. 3266-3271 ◽

Cited By ~ 21

Author(s):

Silvarosa Grassi ◽

Ermelinda Francescangeli ◽

Gianfrancesco Goracci ◽

Vito E. Pettorossi

Keyword(s):

Platelet Activating Factor ◽

Vestibular Nuclei ◽

Long Term Potentiation ◽

Dose Effect ◽

High Frequency Stimulation ◽

Term Potentiation ◽

Presynaptic Mechanisms ◽

The Right

Grassi, Silvarosa, Ermelinda Francescangeli, Gianfrancesco Goracci, and Vito E. Pettorossi. Role of platelet-activating factor in long-term potentiation of the rat medial vestibular nuclei. J. Neurophysiol. 79: 3266–3271, 1998. In rat brain stem slices, we investigated the role of platelet activating factor (PAF) in long-term potentiation (LTP) induced in the ventral part of the medial vestibular nuclei (MVN) by high-frequency stimulation (HFS) of the primary vestibular afferent. The synaptosomal PAF receptor antagonist, BN-52021 was administered before and after HFS. BN-52021 did not modify the vestibular potentials under basal conditions, but it reduced the magnitude of potentiation induced by HFS, which completely developed after the drug wash-out. The same effect was obtained by using CV-62091, a more potent PAF antagonist at microsomal binding sites, but with concentrations higher than those of BN-52021. By contrast both BN-52021 and CV-6209 had no effect on the potentiation once induced. This demonstrates that PAF is involved in the induction but not in the maintenance of vestibular long-term effect through activation of synaptosomal PAF receptors. In addition, we analyzed the effect of the PAFanalogue, 1 - O - hexadecyl - 2 - O - (methylcarbamyl) - sn - glycero - 3phosphocoline (MC-PAF) and the inactive PAF metabolite, 1- O-hexadecyl- sn-glycero-3-phosphocoline (Lyso-PAF) on vestibular responses. Our results show that MC-PAF, but not Lyso-PAF induced potentiation. This potentiation was prevented by d,l-2-amino 5-phosphonopentanoic acid, suggesting an involvement of N-methyl-d-aspartate receptors. Furthermore, under BN-52021 and CV-6209, the MC-PAF potentiation was reduced or abolished. The dose-effect curve of MC-PAF showed a shift to the right greater under BN-52021 than under CV-6209, confirming the main dependence of MC-PAF potentiation on the activation of synaptosomal PAF receptors. Our results suggest that PAF can be released in the MVN after the activation of postsynaptic mechanisms triggering LTP, and it may act as a retrograde messenger which activates the presynaptic mechanisms facilitating synaptic plasticity.

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