Cell Biological Studies of Memory 
kinases in aspects of synaptic physiology such as 
transmitter release. Although the importance of 
tyrosine kinases for synaptic transmission is not 
known, the above findings and the demonstrated 
interaction of tyrosine kinases with serine-threo- 
nine kinases in various nonneuronal signal trans- 
duction pathways led us to investigate whether 
protein tyrosine kinases are involved in the bio- 
chemical events underlying LTP. 
A major limitation in the study of tyrosine ki- 
nases in the brain has been the lack of inhibitors 
of the sort that have proved useful in the study 
of serine-threonine kinases. Recently, several 
groups have developed two classes of inhibitors. 
One class (e.g., genistein) blocks the ATP-bind- 
ing domain, and the other (tyrophostin) blocks 
the substrate-binding domain. These inhibitors 
block tyrosine kinase activity in lymphocytes and 
in other nonneural tissues at concentrations that 
have a negligible effect on serine and threonine 
kinases. To determine whether these inhibitors 
have similar specificity in the brain, O'Dell, 
Grant, and I examined their action on hippocam- 
pal kinase activity. We found that there, too, they 
inhibit tyrosine kinase activity at concentrations 
that have little effect on serine-threonine phos- 
phorylation produced by kinase A, kinase C, and 
CaM kinase. 
We next used four different inhibitors (two 
from each class) to examine LTP produced in the 
CAi neurons. All four blocked the induction of 
LTP. Moreover, their ability to block the facilita- 
tion was related to their effectiveness in blocking 
tyrosine kinase activity. This effect was restricted 
to induction; the inhibitors had no effect on the 
maintenance phase of LTP. Nor did they have an 
effect on the amplitude or duration of post- 
tetanic potentiation. 
We also examined the specificity of the tyro- 
sine kinase inhibitors electrophysiologically and 
found that several forms of synaptic plasticity at- 
tributed to other serine and threonine kinases 
were not affected. The enhanced firing (anti- 
accommodation) produced by norepinephrine 
(which is simulated by cAMP and thought to be 
mediated by kinase A) was not affected by the 
tyrosine kinase inhibitor genistein. Conversely, 
the enhanced firing (anti-accommodation) pro- 
duced by muscarine (which is thought to be me- 
diated by the diacylglycerol-IPj pathway) is in- 
hibited by H-7 but not affected by genistein. 
Finally, the synaptic facilitation induced by phor- 
bol esters and mediated by kinase C, which was 
blocked by H-7, was not affected by the inhibi- 
tors. These data suggest that the induction of LTP, 
or the initial steps in its maintenance, may in- 
volve a tyrosine kinase. We are now trying to ex- 
plore this possibility directly by examining slices 
for changes in tyrosine phosphorylation after in- 
duction of LTP. 
Given the known functions of tyrosine kinases 
in inter- and intracellular signaling processes that 
modulate cell growth, it is notable that the in- 
duction of hippocampal LTP, or learning at other 
synapses, results in growth and morphological 
change of neurons. With the identification of rele- 
vant kinases, their activators, and their substrates, 
the role of tyrosine kinases in synaptic transmis- 
sion and morphological changes accompanying 
learning could be evaluated. 
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