Figure 9. Proposed model of SSA at the synapse level.

In response to low frequency stimulation, presynaptic neurons continuously release neurotransmitters, and the remaining glutamate in the synaptic cleft desensitizes AMPA receptors (AMPARs), resulting in a diminished response to the same amount of glutamate upon subsequent stimulation (A). In response to high frequency stimulation, presynaptic vesicles are depleted of neurotransmitter, compromising neuronal response to subsequent stimuli (B). Neuronal response to repeated stimulation at S1 gradually declines, but response to stimulation of a different synaptic origin at S2 is not influenced by activation history because both presynaptic terminals and postsynaptic receptors at this site are naïve. Thus, SSA appears to result from synaptic depression expressed mostly at the postsynaptic site at low stimulation frequencies but at both presynaptic and postsynaptic sites at high stimulation frequencies.