Figure 3—Idealized pacemaker potentials

Figure 4—Graded response

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)]):

THE MODERN IONIC HYPOTHESIS

Hodgkin, Huxley, and Katz [(3)] and Hodgkin and Huxley [(14)], [(15)], [(16)], in 1952, published a series of papers describing detailed measurements of voltage, current, and time relationships in the giant axon of the squid (Loligo). Hodgkin and Huxley [(17)] consolidated and formalized these data into a set of simultaneous differential equations describing the hypothetical time course of events during spike generation and propagation. The hypothetical system which these equations describe is the basis of the Modern Ionic Hypothesis.

The system proposed by Hodgkin and Huxley is basically one of dynamic opposition of ionic fluxes across the axon membrane. The membrane itself forms the boundary between two liquid phases—the intracellular fluid and the extracellular fluid. The intracellular fluid is rich in potassium ions and immobile organic anions, while the extracellular fluid contains an abundance of sodium ions and chloride ions. The membrane is slightly permeable to the potassium, sodium, and chloride ions; so these ions tend to diffuse across the membrane. When the axon is inactive (not propagating a spike), the membrane is much more permeable to chloride and potassium ions than it is to sodium ions. In this state, in fact, sodium ions are actively transported from the inside of the membrane to the outside at a rate just sufficient to balance the inward leakage. The relative sodium ion concentrations on both sides of the membrane are thus fixed by the active transport rate, and the net sodium flux across the membrane is effectively zero. The potassium ions, on the other hand, tend to move out of the cell; while chloride ions tend to move into it. The inside of the cell thus becomes negative with respect to the outside. When the potential across the membrane is sufficient to balance the inward diffusion of chloride with an equal outward drift, and the outward diffusion of potassium with an inward drift (and possibly an inward active exchange), equilibrium is established. The equilibrium potential is normally in the range of 60 to 65 millivolts.