Hawkins tested this possibility by applying nitric 
oxide to hippocampal slices either alone or coin- 
cident with weak presynaptic stimulation (50 Hz 
for 0.5 s). 
Application of 100 nM nitric oxide alone, presyn- 
aptic stimulation alone, or nitric oxide 5 min after 
presynaptic stimulation ("unpaired" training) pro- 
duced no significant long-term effects on the field 
EPSP recorded in the CAl region. However, when 
nitric oxide was applied at the same time as the pre- 
synaptic stimulation ("paired" training), the synap- 
tic potential was immediately enhanced and re- 
mained enhanced for at least an hour. Paired 
training still produced significant long-term en- 
hancement of the EPSP in the presence of APV, a 
specific blocker of postsynaptic A'^methyl-o-aspar- 
tate (NMDA) receptors, which blocks the induction 
of LTP by tetanic stimulation. 
These results are consistent with the hypothesis 
that nitric oxide acts as a retrograde message with 
activity-dependent presynaptic effects during LTP. 
This mechanism would be formally similar to activity- 
dependent presynaptic facilitation in Aplysia and 
activity-dependent neuromodulation more generally. 
A grant from the National Institute on Aging and 
from the National Institutes of Health provided sup- 
port for the project described above. 
Dr. Kandel is also University Professor, Center 
for Neurobiology and Behavior, Departments of 
Physiology and Psychiatry, Columbia University 
College of Physicians and Surgeons, located at the 
New York Psychiatric Institute. 
Articles 
Abrams, T.W., Karl, K.A., and Kandel, E.R. 1991. 
Biochemical studies of stimulus convergence dur- 
ing classical conditioning in Aplysia: dual regula- 
tion of adenylate cyclase by Ca^^/calmodulin and 
transmitter. /A^ewrosc/ 1 1 :2655-2665. 
Bailey, C.H., Chen, M., Keller, F., and Kandel, E.R. 
1992. Serotonin-mediated endocytosis of apCAM: 
an early step of learning-related synaptic growth 
in Aplysia. Science 256:645-649 
Furukawa, Y., Kandel, E.R., and Pfafifinger, P. 
1992. Three types of early transient potassium 
currents in Aplysia neurons. J Neurosci 12:989- 
1000. 
Glanzman, D.L., Kandel, E.R., and Schacher, S. 
1991. Target-dependent morphological segrega- 
tion of Aplysia sensory outgrowth in vitro. Neu- 
ron 7:903-913. 
Kaang, B K., Pfaffinger, P.J., Grant, S.G.N., Kan- 
del, E.R., and Furukawa, Y. 1992. Overexpres- 
sion of an Aplysia Shaker channel gene modi- 
fies the electrical properties and synaptic efficacy 
of identified Aplysia neurons. Proc Natl Acad Sci 
USA 89:1133-1137. 
Kandel, E.R., and Hawkins, R.D. 1992. The biologi- 
cal basis of learning and individuality. Sci Am 
267:78-86. 
Kandel, E.R., and Squire, L. 1992. Cognitive neuro- 
science: editorial overview. Curr Opin Neuro- 
biol 2:143-145. 
Mayford, M., Barzilai, A., Keller, F., Schacher, S., 
and Kandel, E.R. 1992. Modulation of an NCAM- 
related adhesion molecule with long-term synap- 
tic plasticity in Aplysia. Science 256:638-644. 
O'Dell, T.J., Hawkins, R.D., Kandel, E.R., and Ar- 
ancio, O. 1 99 1 . Tests of the roles of two diffusible 
substances in long-term potentiation: evidence 
for nitric oxide as a possible early retrograde mes- 
senger. Proc Natl Acad Sci USA 88:11285- 
11289. 
O'Dell, T.J., Kandel, E.R., and Grant, S.G.N. 
1991. Long-term potentiation in the hippocam- 
pus is blocked by tyrosine kinase inhibitors. A'ifl- 
fwre 353:558-560. 
Small, S.A., Cohen, T.E., Kandel, E.R., and Haw- 
kins, R.D. 1992. Identified FMRFamide-immuno- 
reactive neuron LPL16 in the left pleural ganglion 
of Aplysia produces presynaptic inhibition of si- 
phon sensory neurons. / Neurosci 1 2: 16 16- 
1627. 
A MULTIFACETED G PROTEIN-COUPLED RECEPTOR BIOASSAY 
Michael R. Lerner, M.D., Ph.D., Associate Investigator 
The superfamily of seven-transmembrane domain 
receptors linked to G proteins provides a major bio- 
logical mechanism for detecting intercellular and 
environmental signals. While the range of ligands 
for these receptors is vast and examples include 
photons, odorants, monoamines, peptides, and pros- 
taglandins, the receptors themselves utilize a variety 
of intracellular signaling systems, such as the activa- 
tion of adenyl cyclase or phospholipase C or the 
inhibition of adenyl cyclase. Because the receptors 
are often situated at control points for crucial activi- 
ties, understanding the molecular basis of how li- 
NEUROSCIENCE 417 
