Alternative Mechanisms For

It seems obvious that if there is an increase in synaptic strength, it must be the result of either an increase in neurotransmitter release or an increase in postsynaptic responsiveness. However, what if it's neither of these? Are there alternative models that can explain synaptic potentiation that involve neither mechanism? Two alternate possibilities have received some attention. They are the possibilities of diminished re-uptake of glutamate, leading to increased synaptic glutamate levels; and altered kinetics of glutamate release, where the same number of glutamate molecules are released but at a faster rate, such that the peak synaptic glutamate concentration is higher.

Does decreased glutamate re-uptake account for LTP? Jonathan Levenson and his collaborators recently directly tested this hypothesis, and the answer was a resounding no. In fact, LTP-inducing stimulation at Schaffer-collateral synapses leads to an increase in glutamate re-uptake through neuronal membrane glutamate

BOX 4—cont'd ALTERNATIVE MECHANISMS FOR LTP

BOX 4 Concentration profile of neurotransmitter delivery determines AMPA receptor activation.

(A) Representation of the experimental design for concurrently stimulating presynaptic release and iontophoretically examining the postsynaptic receptors. Iontophoresis and stimulating electrodes are brought to within 1 mm of an isolated synapse. Filled vertical and horizontal bars, used throughout the figures, represent the fast (1 ms, 100 nA) and slow (10 ms, 10 nA) iontophoretic application parameters.

(B) AMPA receptors are not activated by a slow flux of glutamate. Slow pulses elicited NMDA receptor-only responses, while fast pulses elicited AMPA and NMDA receptor responses from the same site. (AMPA receptor responses are the fast peaks at the beginning of the responses, NMDA receptor responses are the slower, more sustained response.) Because AMPA receptor activation was sensitive to the instantaneous changes in the concentration of neurotransmitter, AMPA-quiet responses could be generated at synapses with functional AMPA Receptors. (C) Silent synapses contain functional AMPA receptors. Excitatory Post-Synaptic Current (EPSC) AMPA-quiet responses, resulting from endogenous transmitter release, were evoked by presynaptic electrical stimulation at a synapse in a cultured hippocampal neuron (open vertical bars). Evoked synaptic events were interleaved with alternating iontophoretic applications of neurotransmitter. Although EPSCs AMPA-quiet were evoked presynap-tically, AMPA receptor responses were clearly visible at this synapse during fast iontophoretic pulses, indicating that endogenous AMPA-quiet synaptic events occurred at synapses containing functional AMPARs (n = 4). Figure and figure legend from Renger, Egles, and Liu (29).

transporters (28). This counterintuitive effect may be involved in limiting glutamate spillover from potentiated synapses. An alternative possibility is that increased re-uptake might protect potentiated synapses from desensitization, if there would otherwise be a too-prolonged elevation of glutamate at the synapse.

Certain aspects of the second alternative, the "altered kinetics of release"

BOX 4—cont'd ALTERNATIVE MECHANISMS FOR LTP

hypothesis, have also been evaluated experimentally. Renger, Egles, and Liu (29) found that rapid elevations of glutamate at the synapse are more effective at activating synaptic AMPA receptors than are slower elevations. There are several reasons why rapid elevations of glutamate might be particularly efficacious. For any given number of glutamate molecules, more rapid release of glutamate will give a higher peak glutamate level. This factor is compounded by the kinetics of glutamate binding to AMPA receptors and receptor desensitization—AMPA receptors have a fast on-rate of glutamate binding and also rapidly desensitize. Thus, a slow elevation of glutamate concentration in the synapse can lead to desensitization of a fraction of the AMPA receptors before the peak glutamate concentration is reached. Overall, the model is that rapid, transient elevations of synaptic glutamate cause greater AMPA receptor responses so that simply changing the kinetics of glutamate release, without changing the total number of glutamate molecules released, leads to a net synaptic potentiation (see figure). Thus, all of LTP might be accounted for by speeding up the presynaptic release process itself. While this hypothesis is at a very early stage of testing, it is an intriguing idea. I also find it interesting that the increased rate of glutamate re-uptake observed by Levenson et al. (28) is also consistent with this idea—increased re-uptake may serve to sharpen the peak of glutamate at the synapse and diminish AMPA receptor desensitization.

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