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BBB seminar: Nigel J. Emptage

Ca2+ imaging as a reporter of neural activity in hippocampal neurones

Nigel J. Emptage
Department of Pharmacology, University of Oxford, UK

Long-term potentiation (LTP) is an activity-dependent form of synaptic plasticity regarded by many as the synaptic basis of learning and memory. A considerable amount of work has been conducted in order to understand the mechanisms by which LTP is expressed. Although some features of LTP expression are generally agreed upon many are not. One factor that adds to the complexity of the analysis is identifying the contribution made by individual synapses when the output of a neurone comprises of a contribution from many. Optical approaches, combined with electrophysiology, offer exciting new opportunities to dissect apart this problem. The use of fluorescence microscopy in particular has provided opportunities with which one can monitor synaptic transmission at discrete locations within the cell.

Emptage et al. (1) used confocal fluorescence microscopy to characterise the Ca2+ rise in dendritic spines following synaptic stimulation. They concluded that the transient results from glutamate activation of NMDA-Rs. Thus synaptically-evoked Ca2+ transients in dendritic spines can be used as a measure of transmitter release. Subsequent analysis of changes that occur following induction of LTP revealed that the probability of observing the Ca2+ transient (PCa ) increased after LTP induction (2) . This is consistent with the idea that at least one expression mechanism of LTP is an increase in the probability of transmitter release
(Pr ). Other mechanisms are also thought to contribute to LTP expression, for example, the unmasking of silent synapses (3) , thus imaging approaches were used to explore the changes that occur on unmasking. Ward et al. (4) showed that silent synapses do not undergo a change in PCa when LTP is induced, but instead undergo a tetanus toxin sensitive post-synaptic unmasking process. Interestingly, once activated previously silent synapses do show an increase in PCa when potentiated for a second time. It therefore appears that the LTP expression mechanism is state-dependent.

Although the mechanisms that underlie the post-synaptic unmasking process at silent synapses have been extensively examined, the mechanistic basis of changes in Pr are not well understood. We have again used fluorescence imaging methods in an attempt to tease apart this process. It is widely accepted that the level of intracellular Ca2+ in the pre-synaptic terminal plays an important role in the regulation of neurotransmitter release. We observe that the Ca2+ transient in the pre-synaptic terminal varies widely in amplitude, consistent with the idea that Ca2+ transient variability drives stochastic transmitter release. However, the variability appears to be neurotransmitter dependent, as it is abolished by the vesicular proton ATPase inhibitor bafilomycin A1. Thus variations in pre-synaptic Ca2 + transients appear to modulate transmitter release, not regulate Pr. In light of this result we are now using additional imaging methods as a means of understanding the basis of Pr. These developments will be discussed in the presentation.

Acknowledgements: The author gratefully acknowledges the support of the MRC (UK).

References:

1. Emptage NJ, Bliss TVP, Fine A (1999) Neuron. 22:115-24

2. Emptage NJ, Reid C, Fine A, Bliss TVP (2003) Neuron 38:797-804

3. Isaac JT, Nicoll RA, Malenka RC (1995) Neuron 15:427-34

4. Ward B, McGunness L, Akerman C, Fine A, Bliss TVP, Emptage NJ (2006) Neuron 52:649-61

Host: Clive Bramham <clive.bramham@biomed.uib.no>, Dept. of Biomedicine