When an action potential reaches a synaptic terminal, fusion of a transmitter-containing vesicle with the presynaptic membrane occurs with a probability (pr) of less than one. Despite the fundamental importance of this parameter, pr has not been directly measured in the central nervous system. Here we describe a novel approach to determine pr, monitoring the decrement of NMDA (N-methyl-D-aspartate)-receptor mediated synaptic currents in the presence of the use-dependent channel blocker MK-801 (ref. 2). On a single postsynaptic CA1 hippocampal slice neuron, two classes of synapses with a sixfold difference in pr are resolved. Synapses with low pr contribute to over half of transmission and are more sensitive to drugs enhancing transmitter release. Switching between these two classes of synapses provides the potential for large changes in synaptic efficacy and could underlie forms of activity-dependent plasticity.

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Mechanisms of potentiation by calcium-calmodulin kinase II of postsynaptic sensitivity in rat hippocampal CA1 neurons. J. Neurophysiol. 78: 2682-2692, 1997. Preactivated recombinant alpha-calcium-calmodulin dependent multifunctional protein kinase II (CaMKII*) was perfused internally into CA1 hippocampal slice neurons to test the effect on synaptic transmission and responses to exogenous application of glutamate analogues. After measurement of baseline transmission, internal perfusion of CaMKII* increased synaptic strength in rat hippocampal neurons and diminished the fraction of synaptic failures. After measurement of baseline responses to applied transmitter, CaMKII* perfusion potentiated responses to kainate but not responses to N-methyl--aspartate. Internal perfusion of CaMKII*potentiated the maximal effect of kainate. Potentiation by CaMKII* did not change the time course of responses to kainate, whereas increasing response size by pharmacologically manipulating desensitization or deactivation rate constants significantly altered the time course of responses. Nonstationary fluctuation analysis of responses to kainate showed a decrease in the coefficient of variation after potentiation by CaMKII*. These data support the hypothesis that CaMKII increases postsynaptic responsiveness by increasing the available number of active alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate channels and suggests that a similar process may occur during the expression of long-term potentiation.