Trends in Neurosciences
Extrasynaptic glutamate spillover in the hippocampus: evidence and implications
Section snippets
How does LTP shed light on AMPA-silent signalling?
Pairing presynaptic stimulation of apparently AMPA-silent synapses with postsynaptic depolarization to around 0 mV, to maximize Ca2+ influx via NMDA receptors, can uncover an AMPA receptor-mediated component6, 7. This coincides nicely with several previous observations on the mechanisms of expression of NMDA receptor-dependent LTP: several groups have reported LTP to be expressed preferentially, if not exclusively, by an increase in the size of the AMPA receptor-mediated signal, and to be
Glutamate spillover explains LTP of NMDA receptor-mediated signals
We have recently presented two lines of argument in favour of the spillover hypothesis for excitatory transmission. The first approach relies on a closer examination of the changes in the AMPA and NMDA receptor-mediated signals with LTP ([20]). We found that LTP of AMPA-receptor-mediated signals, elicited by pairing afferent stimulation with depolarization, is consistently associated with a small potentiation of NMDA-receptor-mediated signals, and that this can be accounted for by an increase
Effects of recording temperature on `AMPA-silent' signalling
The second body of evidence against the `latent AMPA-receptor cluster' hypothesis, and in favour of glutamate spillover, comes from an examination of the effect of altering the recording temperature[22]. The studies described above were almost entirely performed at room temperature, which might have widespread consequences for the regulatory processes affecting synaptic transmission. Repeating the comparison of quantal contents mediated by AMPA and NMDA receptors at physiological temperature
Implications of the spillover hypothesis
The spillover hypothesis has extensive consequences, both for the interpretation of experiments on glutamatergic transmission, and for the understanding of the normal functioning of the brain. Consider the possible arrangements of excitatory synapses illustrated in Fig. 3: these differ according to whether or not the presynaptic bouton is invaded by an action potential, transmitter release takes place, and the bouton is in synaptic contact with the recorded postsynaptic cell. Both AMPA and NMDA
Discrepancies in the literature
Thus far, the spillover model is consistent with the experimental data described above. There is, however, considerable disagreement about whether, and to what extent, potentiation of the NMDA receptor-mediated component accompanies conventional LTP: while some groups have reported no change23, 24, others have described either a relatively modest potentiation[25] or even an increase equivalent to that of the AMPA receptor-mediated component[26]. Some of this disagreement can be explained by the
Postsynaptic changes in AMPA receptors
An additional factor that determines the relative potentiation of AMPA- and NMDA-receptor-mediated signals is the degree to which changes in quantal amplitude accompany the increase in quantal content. Many groups have indeed reported increases in the quantal amplitude of AMPA receptor-mediated signals with LTP (10, 11, 35, 36). Although this is not a unanimous finding37, 38, it provides some of the most compelling evidence that LTP expression involves a postsynaptic change. A relatively simple
Problems with the spillover hypothesis
How can one reconcile the pathway specificity of LTP with the spillover hypothesis? It is generally accepted that if two separate populations of afferents converge on the same postsynaptic neurons, only the pathway that is paired with depolarization undergoes potentiation[42]. If, however, the immediately apposed presynaptic bouton in synapse D is activated by a second stimulus pathway, what is to prevent pairing of the first pathway with postsynaptic depolarization from eliciting LTP at this
Further implications of spillover
Another consequence of the spillover hypothesis is that it could complicate the use of the NMDA-receptor open-channel blocker MK-801 as a quantitative tool to study presynaptic transmitter release probability52, 53: the opening probability of a given NMDA receptor could be a complicated function of the probability not only at the immediately apposed release site, but also at all the neighbouring sites that are close enough for significant spillover. This does not necessarily invalidate its use
Could glutamate spillover occur in the living brain?
We have argued that the discrepancy in quantal content at physiological temperature is less than at room temperature, although not completely abolished[22]. It is difficult to extrapolate from hippocampal slices in vitro to the intact brain, but if spillover does occur, it raises the possibility that excitatory synapses do not function as entirely private communication channels between individual neurones. Another consequence is that a given cell could sample a different population of
Concluding remarks
In this review we have considered how glutamate spillover could explain the mismatch in the behaviour of the two components of fast excitatory synaptic signalling at some hippocampal and neocortical synapses. We cannot, of course, exclude the alternative interpretation, that functional AMPA receptors are absent at a population of synapses, and the evidence that distinguishes between these hypotheses is indirect. It remains to be determined whether the discrepancy between AMPA and NMDA
References (57)
- et al.
Neuron
(1991) - et al.
Neuron
(1990) - et al.
Neuron
(1995) - et al.
Neuron
(1997) - et al.
Neuron
(1995) - et al.
Neuron
(1994) - et al.
Neurosci. Lett.
(1992) - et al.
Neuron
(1996) - et al.
Neuron
(1997) - et al.
Neuron
(1988)
Neuron
Dev. Brain Res.
Neuroscience
Trends Neurosci.
Trends Neurosci.
Neuron
Neuron
Trends Neurosci.
Biophys. J.
Neuron
Nature
Nature
Neuron,
Nature
Trends Neurosci.
Nature
Nature
Neuron
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