And just as I was beginning to think in this direction, Seth Grant and Mark Mayford came in the lab. In fact, I may be being unfair, maybe some of my thinking evolved because they were in the lab and talking about this. And so we decided to go ahead and try to dissect out signalling pathways and see whether we can dissect LTP and memory storage and relate them to one another.

Now Seth Grant was very much interested in the tyrosine kinase pathway, a very important second messenger pathway that we had never [explored] in Aplysia. And he had a quite good inhibitor for tyrosine kinase, and when we used that, we blocked LTP. Now there are a number of tyrosine kinases, and he was able to get genetic knockouts for the four major tyrosine kinases. And we explored all of these, and LTP and memory storage, and none of them had any effect except for one: the knockout of the fyn tyrosine kinase. That was quite beautiful. Eliminated LTP, and eliminated memory storage. That was wonderful, knocking out a single gene, selective interference, with, you know, tyrosine kinase pathway, and at the same time with this one molecular knockout to get rid of memory storage in the hippocampus.

And Richard Axel was chairman of a symposium at Cold Spring Harbor, and he invited me to present this, and he also invited Susumu Tonegawa who'd made a parallel observation. Susumu did an analogous experiment. He knocked out CaM kinase II with the gene knockout. Found it interfered with LTP, and also found that it interfered with memory storage. So here we had a breakthrough, it was really quite inspiring.

And that got me really interested in trying to dissect things a little bit more finely. And I thought I would begin by exploring LTP. And one of the things that I'd found very powerful in Aplysia was the fact that synaptic facilitation had an early phase, which did not require protein synthesis, and a late phase that did, and so we began to explore LTP, and we found a similar thing. There's an early phase, produced by a single train that was protein synthesis-independent, a late phase that was protein synthesis-dependent. The early phase did not require cyclic AMP—it was very different than in Aplysia. It required CaM kinase, calcium influx, etcetera. But the late phase required the cyclic AMP-dependent protein kinase, and it required not serotonin as a modulator, but dopamine acting through D1, D5 receptors. So that got us quite inspired to seeing whether we could really home in a little bit better on LTP.