How the Brain Modifies Its Own Circuits, 
Synaptic Neuromodulation 
Charles F. Stevens, M.D., Ph.D. — Investigator 
Dr. Stevens is also Professor of Molecular Neurobiology at the Salk Institute and Adjunct Professor of 
Pharmacology at the University of California, San Diego. He received his B.A. degree in psychology at 
Harvard University, his M.D. degree at Yale University, and his Ph.D. degree in biophysics at the Rocke- 
feller University for studies with Keffer Hartline. He was a member of the faculties at the University of 
Washington Medical School and at Yale Medical School before joining the Salk Institute. Dr. Stevens is a 
member of the National Academy of Sciences. 
A remarkable feature of the brain is its ability 
to modify itself. Neuronal activity can 
change the properties of nerve cells so that the 
neural circuits responsible for the brain's com- 
putations become physically different. This abil- 
ity is termed neuromodulation. 
To understand neuromodulation one must 
have an idea of how neuronal circuits are con- 
structed and how signals are passed from one 
brain cell (neuron) to another in these circuits. 
Each neuron in the brain receives information 
from about 10,000 neurons and, in turn, sends 
information to about 10,000 others. Information 
is transmitted from one nerve cell to the next at 
special points of contact known as synapses. 
Neural circuits, then, are formed by chains of neu- 
rons that are interconnected at synaptic contacts 
in incredibly complicated ways. 
Each time a nerve impulse arrives at a synapse, 
the sending cell releases a small quantity of a 
chemical known as a neurotransmitter. The neu- 
rotransmitter diffuses rapidly — in less than a 
thousandth of a second — to the receiving neu- 
ron, where it binds onto special proteins, called 
receptors, embedded in the receiving cell's sur- 
face membrane. When the neurotransmitter 
binds onto the receptor, it causes it to change 
shape and to reveal a submicroscopic pore 
through which an electric current can flow. This 
current, carried by ions, constitutes the signal 
within the receiving neuron and is used to deter- 
mine when the receiving cell itself will produce 
impulses. 
Two large classes of receptors are known -, excit- 
atory and inhibitory. In the receiving neuron, ex- 
citatory receptors cause changes that tend to pro- 
duce nerve impulses, and the inhibitory 
receptors do the opposite: they prevent the gener- 
ation of nerve impulses. Thus the two classes of 
synapses act as an accelerator and a brake on 
nerve cell activity. About two-thirds of the syn- 
apses in the brain are excitatory, and the rest are 
inhibitory. 
An important determinant of how the circuits 
function is the strength of the various synaptic 
contacts. If a synapse is strong, it will be effective 
in helping to produce (or prevent, if inhibitory) 
nerve impulses in the receiving cell, whereas 
weak synapses will be much less effective. 
Clearly, what a neuronal circuit computes will 
depend on the strengths of its various synapses. 
Our laboratory has discovered that the strength 
of excitatory synapses is under control of the 
brain activity itself. Thus the efficiency with 
which one neuron transmits information to an- 
other is subject to neuromodulatory control of 
still other neurons. This control is quite specific 
and can be targeted to particular neurons in a 
circuit. 
The mechanism of this neuromodulatory con- 
trol is a version of one very common in biochem- 
istry. A special enzyme known as protein kinase A 
(PKA) adds a phosphate group to the receptor, 
and this modified receptor then has a greater ef- 
fect on the receiving neuron. To understand this 
mechanism more completely requires some addi- 
tional information about how receptors work. 
When the receptor binds its neurotransmitter 
— glutamate, in the case of the excitatory recep- 
tors — and opens its pore for ions to flow through, 
the receptor usually remains in its open state for 
about a thousandth of a second. Techniques are 
available that permit the neurobiologist to record 
the currents that flow through single receptors so 
that we can observe them as they open and close. 
When PKA is applied to small patches of mem- 
brane containing excitatory receptors, these re- 
ceptors are modified: the altered (phosphory- 
lated) receptors dwell in the open state 5 to 10 
times longer than usual, and the signal received at 
the synapse is 5 to 10 times larger for each im- 
pulse arrival. The increased strength thus occurs 
through increases in the open time of the 
receptors. 
But what controls the PKA? Our laboratory has 
found some, but not all, of the answers to this 
question. PKA is activated by a rather compli- 
cated cascade of events that involve the familiar 
messenger molecule cAMP. This cascade is ulti- 
mately engaged by the action of chemicals known 
as neuromodulators that are released by other 
neurons when they are active. Many neuromodu- 
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