Neurons in the brain are often linked by single synaptic contacts (Gulyás et al., 1993) and the probabilistic character of synaptic activity makes it desirable to increase the resolution of physiological experiments by observing the function of the smallest possible number of synaptic terminals, ideally, one. Because they are critically important and technically difficult to resolve, several of the core questions investigated in singe-site experiments have been under study for decades (Auger and Marty, 2000). Many approaches have been taken toward the goal of measuring activity at few synapses, and consideration of the capabilities and limitations of each of these methods permits a review of the contributions each has made possible to present understanding of synaptic function. A number of methodological advances in recent years have increased resolving power. New techniques often build on previous developments and many effective approaches combine components of existing specialized methods with new technology. One theme that emerges is that synaptic properties vary among regions, reducing the utility of general questions such as whether synaptic glutamate saturates receptors or how rapidly synaptic vesicle pools are depleted. For several core questions, multiple studies using different methods have reached similar conclusions, suggesting that consensus may be emerging for some anatomic synapses.
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