Eye, Brain, and Vision

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 infor-
mation 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 im-
pulses 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 initi-
ated 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 chemi-
cal 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, so-
dium, and calcium ions (Cl , K+, Na+ and Ca 2+.
In the resting state, the inside and outside of the cell differ in electrical poten-
tial 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 concen-
trations 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 posi-
tively 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. Potas-
sium 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 argu-
ment, 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 calcu-
late what the membrane potential is, we have to know the relative concentra-
tions 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 posi-
tive 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 domi-
nate 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 identi-
cal 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 incap-
able 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 potas-
sium 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 trans-
ferred 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 depolariza-
tion but because many potassium pores are already open, enough potassium