Bullock (7), (10), (12), (13) has demonstrated the existence of a third type of subthreshold response, which he calls the graded response. While the postsynaptic membrane is quite often electrically inexcitable, other regions of the somatic and dendritic membranes appear to be moderately excitable. It is in these regions that Bullock observes the graded response. If one applies a series of pulsed voltage stimuli to the graded-response region, the observed responses would be similar to those shown in Figure 4A. Plotting the peak response voltage as a function of the stimulus voltage would result in a curve similar to that in Figure 4B (see Ref. 3, page 4). For small values of input voltage, the response curve is linear; the membrane is passive. As the stimulus voltage is increased, however, the response becomes more and more disproportionate. The membrane is actively amplifying the stimulus potential. At even higher values of stimulus potential, the system becomes regenerative; and a full action potential results. The peak amplitude of the response depends on the duration of the stimulus as well as on the amplitude. It also depends on the rate of application of the stimulus voltage. If the stimulus potential is a voltage ramp, for example, the response will depend on the slope of the ramp. If the rate of rise is sufficiently low, the membrane will respond in a passive manner to voltages much greater than the spike threshold for suddenly applied voltages. In other words, the graded-response regions appear to accommodate to slowly varying potentials. In terms of functional operation, we can think of the synapse as a transducer. The input to this transducer is a spike or series of spikes in the presynaptic axon. The output is an accumulative, long-lasting potential which in some way (perhaps not uniquely) represents the pattern of presynaptic spikes. The pacemaker appears to perform the function of a clock, producing periodic spikes or spike bursts or producing periodic changes in the over-all excitability of the neuron. The graded-response regions appear to act as nonlinear amplifiers and, occasionally, spike initiators. The net result of this electrical activity is transformed into a series of spikes which originate at spike initiation sites and are propagated along axons to other neurons. The electrical activity in the neuron described above is summarized in the following outline (taken in part from Bullock (7)): 1. Synaptic Potentials a. Excitatory or inhibitory b. Facilitated, antifacilitated, or neither c. With excitatory aftereffect, inhibitory aftereffect, neither, or both 2. Pacemaker Potentials a. Relaxation type, undulatory type, or none at all b. Producing single spike, spike burst, or no spikes c. Rhythmic or sporadic 3. Graded Response (rate sensitive) 4. Spike Initiation THE MODERN IONIC HYPOTHESIS