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A synapse appears as the thin, dark area near the bottom center in this electron microscope picture of a section through cerebellar cortex of a rat. To the left of the synapse, an axon cut in cross section is filled with tiny round synaptic vesicles, in •which neurotransmitter is stored. To the right a dendritic process (called a spine) can be seen coming off of a large dendritic branch, which runs horizontally across the picture near the top. (The two sausage-like dark structures in this dendrite are mitochondria.) The two membrane surfaces, of the axon and dendrite, come together at the synapse, where they are thicker and darker. A 20-nanomctcr cleft separates them.
Top: A segment of nerve axon at rest. The sodium pump has expelled most sodium ions and brought in potassium ions. Sodium channels are mainly closed. Because many potassium channels are open, enough potassium ions have left relative to those entering to charge the membrane to 70 millivolts positive outside. Bottom: A nerve impulse is traveling from left to right. At the extreme right the axon is still in the resting state. In the middle section the impulse is in full swing: sodium channels are open, sodium ions are pouring in (though not in nearly large enough amounts to produce any measurable changes in concentration in the course of one impulse); the membrane is now 40 millivolts, negative outside. At the extreme left the membrane is recovering. The resting potential is restored, because more potassium channels have opened (and then closed) and because sodium channels have automatically closed. Because sodium channels cannot immediately reopen, a second impulse cannot occur for about a millisecond. This explains why the impulse when under way cannot travel back toward the cell body.

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IMPULSES, SYNAPSES, AND CIRCUITS

A large part of neuroscience concerns the nuts and bolts of the subject: how single cells work and how information is conveyed from cell to cell across synapses. It should be obvious that without such knowledge we are in the position of someone who wants to understand the workings of a radio or TV but does not know anything about resistors, condensers, or transistors. In the last few decades, thanks to the ingenuity of several neurophysiologists, of whom the best known are Andrew Huxley, Alan Hodgkin, Bernard Katz, John Eccles, and Stephen Kuffler, the physicochemical mechanisms of nerve and synaptic transmission have become well understood. It should be equally obvious, however, that this kind of knowledge by itself cannot lead to an understanding of the brain, just as knowledge about resistors, condensers, and transistors alone will not make us understand a radio or TV, or knowledge of the chemistry of ink equip us to understand a Shakespeare play.
In this chapter I begin by summing up part of what we know about nerve conduction and synaptic transmission. To grasp the subject adequately, it is a great help to know some physical chemistry and electricity, but I think that anyone can get a reasonable feel for the subject without that. And in any case you only need a very rudimentary understanding of these topics to follow the subsequent chapters.
The job of a nerve cell is to take in information from the cells that feed into it, to sum up, or integrate, that information, and to deliver the integrated information to other cells. The information is usually conveyed in the form of brief events called nerve impulses. In a given cell, one impulse is the same as any other; they are stereotyped events. At any moment a cell's rate of firing impulses is determined by information it has just received from the cells feeding into it, and its firing rate conveys information to the cells that it in turn feeds into. Impulse rates vary from one every few seconds or even slower to about 1000 per second at the extreme upper limit.


                               THE MEMBRANE POTENTIAL
     What happens when information is transferred from one cell to another at the synapse? In the first cell, an electrical signal, or impulse, is initiated on the part of an axon closest to the cell body. The impulse travels down the axon to its terminals. At each terminal, as a result of the impulse, a chemical is released into the narrow, fluid-filled gap between one cell and the next—
the synoptic cleft—and diffuses across this 0.02-micrometer gap to the second, postsynaptic, cell. There it affects the membrane of the second cell in such a way as to make the second cell either more or less likely to fire impulses. That is quite a mouthful, but let's go back and examine the process in detail.
The nerve cell is bathed in and contains salt water. The salt consists not only of sodium chloride, but also of potassium chloride, calcium chloride, and a few less common salts. Because most of the salt molecules are ionized, the fluids both inside and outside the cell will contain chloride, potassium, sodium, and calcium ions (Cl , K+, Na+ and Ca 2+.
In the resting state, the inside and outside of the cell differ in electrical potential by approximately one-tenth of a volt, positive outside. The precise value is more like 0.07 volts, or 70 millivolts. The signals that the nerve conveys consist of transient changes in this resting potential, which travel along the fiber from the cell body to the axon endings. I will begin by describing how the charge across the cell membrane arises.
The nerve-cell membrane, which covers the entire neuron, is a structure of extraordinary complexity. It is not continuous, like a rubber balloon or hose, but contains millions of passages through which substances can pass from one side to the other. Some are pores, of various sizes and shapes. These are now known to be proteins in the form of tubes that span the fatty substance of the membrane from one side to the other. Some are more than just pores; they are little machine-like proteins called pumps, which can sieze ions of one kind and bodily eject them from the cell, while bringing others in from the outside.
This pumping requires energy, which the cell ultimately gets by metabolizing glucose and oxygen. Other pores, called channels, are valves that can open and close. What influences a given pore to open or close depends on what kind of pore it is. Some are affected by the charge across the membrane; others open or close in response to chemicals floating around in the fluid inside or outside the cell.
The charge across the membrane at any instant is determined by the concentrations of the ions inside and out and by whether the various pores are open or closed. (I have already said that pores are affected by the charge, and now I am saying that the charge is determined by the pores. Let's just say for now that the two things can be interdependent. I will explain more soon.) Given the existence of several kinds of pores and several kinds of ions, you can see that the system is complicated. To unravel it, as Hodgkin and Huxley did in 1952, was an immense accomplishment.
First, how does the charge get there? Suppose you start with no charge across the membrane and with the concentrations of all ions equal inside and outside. Now you turn on a pump that ejects one kind of ion, say sodium, and for each ion ejected brings in another kind, say potassium. The pump will not in itself produce any charge across the membrane, because just as many positively charged ions are pumped in as are pumped out (sodium and potassium ions both having one positive charge). But now imagine that for some reason a large number of pores of one type, say the potassium pores, are opened. Potassium ions will start to flow, and the rate of flow through any given open pore will depend on the potassium concentrations: the more ions there are near a pore opening, the more will leak across, and because more potassium ions are inside than outside, more will flow out than in. With more charge leaving than entering, the outside will quickly become positive with respect to the inside.
This accumulation of charge across the membrane soon tends to discourage further potassium ions from leaving the cell, because like charges repel one another. Very quickly—before enough K+ ions cross to produce a measurable change in the potassium concentration—the positive-outside charge builds up to the point at which it just balances the tendency ofK+ ions to leave. (There are more potassium ions just inside the pore opening, but they are repelled by the charge.) From then on, no net charge transfer occurs, and we say the system is in equilibrium. In short, the opening of potassium pores results in a charge across the membrane, positive outside.
Suppose, instead, we had opened the sodium pores. By repeating the argument, substituting "inside" for "outside", you can easily see that the result would be just the reverse, a negative charge outside. If we had opened both types of pores at the same time, the result would be a compromise. To calculate what the membrane potential is, we have to know the relative concentrations of the two ions and the ratios of open to closed pores for each ion—and then do some algebra.


                                            THE IMPULSE
     When the nerve is at rest, most but not all potassium channels are open, and most sodium channels are closed; the charge is consequently positive outside. During an impulse, a large number of sodium pores in a short length of the nerve fiber suddenly open, so that briefly the sodium ions dominate and that part of the nerve suddenly becomes negative outside, relative to inside. The sodium pores then reclose, and meanwhile even more potassium pores have opened than are open in the resting state. Both events—the sodium pores reclosing and additional potassium pores opening—lead to the rapid restoration of the positive-outside resting state. The whole sequence lasts about one-thousandth of a second.
All this depends on the circumstances that influence pores to open and close.
For both Na+ and K+ channels, the pores are sensitive to the charge across the membrane. Making the membrane less positive outside—depolarizing it from its resting state—results in the opening of the pores. The effects are not identical for the two kinds of pores: the sodium pores, once opened, close of their own accord, even though the depolarization is maintained, and are then incapable of reopening for a few thousandths of a second; the potassium pores stay open as long as the depolarization is kept up. For a given depolarization, the number of sodium ions entering is at first greater than the number of potassium ions leaving, and the membrane swings negative outside with respect to inside; later, potassium dominates and the resting potential is restored.
In this sequence of events constituting an impulse, in which pores open, ions cross, and the membrane potential changes and changes back, the number of ions that actually cross the membrane—sodium entering and potassium leaving—is miniscule, not nearly enough to produce a measurable change in the concentrations of ions inside or outside the cell. In several minutes a nerve might fire a thousand times, however, and that might be enough to change the concentrations, were it not that the pump is meanwhile continually ejecting sodium and bringing in potassium so as to keep the concentrations at their proper resting levels. The reason that during an impulse such small charge transfers result in such large potential swings is a simple matter of electricity:
the capacitance of the membrane is low, and potential is equal to charge transferred divided by capacitance.
A depolarization of the membrane—making it less positive-outside than it is at rest—is what starts up the impulse in the first place. If, for example, we suddenly insert some sodium ions into the resting fiber, causing a small initial depolarization, a few sodium pores open as a consequence of that depolarization but because many potassium pores are already open, enough potassium

   
 
 
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This cross-sectional microscopic drawing of the nerve cells in the retina was made by Santiago Ramon y Cajal, the greatest neuroanatomist of all time. From the top, where the slender rods and fatter cones are shown, to the bottom, where optic nerve fibers lead off to the right, the retina measures one-quarter millimeter.
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