Quantifying the magnitude of changes in synaptic level parameters with long-term potentiation

Experimental evidence supports a number of mechanisms for the synaptic change that occurs with long-term potentiation (LTP) including insertion of AMPA receptors, an increase in AMPA receptor single channel conductance, unmasking silent synapses, and increases in vesicle release probability. Here we combine experimental and modeling studies to quantify the magnitude of the change needed at the synaptic level to explain LTP with these proposed mechanisms. Whole cell patch recordings were used to measure excitatory postsynaptic potential (EPSP) amplitude in response to near minimal afferent stimulation before and after LTP induction in CA1 pyramidal cells. Detailed neuron and synapse level models were constructed to estimate quantitatively the changes needed to explain the experimental results. For cells in normal artificial cerebrospinal fluid (ACSF), we found a 60% average increase in EPSP amplitude with LTP. This was explained in the models by a 63% increase in the number of activated synapses, a 64% increase in the AMPA receptor single channel conductance, or a 73% increase in the number of AMPA receptors per potentiated synapse. When the percentage LTP was above the average, the required increases through the proposed mechanisms became nonlinear, particularly for increases in the number of receptors. Given constraints from other experimental studies, our quantification suggests that neither unmasking silent synapses nor increasing the numbers of AMPA receptors at synapses is sufficient to explain the magnitude of LTP we observed, but increasing AMPA single channel conductance or vesicle release probability can be sufficient. Our results are most compatible with a combination of mechanisms producing LTP.