In Search of Memory: The Emergence of a New Science of Mind

by Eric R. Kandel

At the time of my birth, Vienna was the most important cultural center in the German-speaking world, rivaled only by Berlin, capital of the Weimar Republic.

Thus we confirmed our idea that one of the functions of repeated sensitization training—why practice makes perfect—is to cause the appropriate signals in the form of kinases to move into the nucleus.

Once in the nucleus, what do these kinases do? We knew from recently published studies of non-neuronal cells that protein kinase A can activate a regulatory protein called CREB (cyclic AMP response element-binding protein), which binds to a promoter (the cyclic AMP response element).

In 1995 Bartsch found that there are in fact two forms of the CREB protein, much as the model of Jacob and Monod might have predicted: one that activates gene expression (CREB-1), and one that suppresses gene expression (CREB-2). Repeated stimulation causes protein kinase A and MAP kinase to move to the nucleus, where protein kinase A activates CREB-1 and MAP kinase inactivates CREB-2. Thus long-term facilitation of synaptic connections requires not only a switching on of some genes, but also the switching off of others (figure 19–1).

Second, we were seeing Sherrington’s discovery of the integrative action of the neuron carried to the level of the nucleus. I was amazed by the parallels: on the cellular level, excitatory and inhibitory synaptic signals converge on a nerve cell, while on the molecular level, one CREB regulatory protein facilitates gene expression and the other inhibits it.

Conversely, a characteristic of age-related memory loss (benign senescent forgetfulness) is the inability to consolidate long-term memories. This defect of aging may represent not only a weakening of the ability to activate CREB-1, but also an insufficiency of signals to remove the braking action of CREB-2 on memory consolidation.

Even more fascinating, mutant flies bred to produce more copies of the CREB activator had the equivalent of flashbulb memories.

We hypothesized that the transient modification of a given synapse produced by short-term memory would somehow mark that synapse. Marking would allow proteins to be recognized by and stabilized at that synapse.

We simulated behavioral training as before by applying pulses of serotonin, but now we could apply them selectively to one or the other set of synaptic connections. A single pulse of serotonin applied to one set of synapses produced short-term facilitation in those synapses only, as expected. Yet five pulses of serotonin applied to one set of synapses produced long-lasting facilitation and growth of new synaptic terminals only at the stimulated synapses.

Our findings now indicated that one function of local protein synthesis is to sustain the long-term strengthening of the synaptic connection. When we inhibited local protein synthesis at a synapse, the process of long-term facilitation began and new terminals grew, making use of the proteins sent to the synapse from the cell body.

Prions were a major field of study in yeast, but no one had identified a normal function of these proteins until Kausik’s discovery of the novel form of CPEB in neurons. Thus his discovery not only offered deep new insights into learning and memory, it broke new ground in biology. We soon found that in the sensory neurons of the gill-withdrawal reflex, the conversion of CPEB from the inactive, non-propagating form to the active, propagating form is controlled by serotonin, the transmitter that is required for converting short- to long-term memory (figure 19–4). In its self-perpetuating form, CPEB maintains local protein synthesis. Moreover, the self-perpetuating state is not easily reversed.

First, a normal physiological signal—serotonin—is critical for converting CPEB from one form to another. Second, CPEB is the first self-propagating form of a prion known to serve a physiological function—in this case, perpetuation of synaptic facilitation and memory storage.

Everyone was calling—radio, television, newspapers, our friends. I found the telephone calls from Vienna most interesting because they were calling to tell me how pleased Austria was that there was yet another Austrian Nobel Prize. I had to remind them that this was an American Nobel Prize.

Eduard Pernkopf, the dean of the medical school of the University of Vienna, meets his faculty in April 1938, several weeks after Hitler’s entry into Vienna. The dean and the organized faculty greet one another with “Heil Hitler!”

The life of a biological scientist in the United States is a life of discussion and debate—it is the Talmudic tradition writ large. But rather than annotate a religious text, we annotate texts written by evolutionary processes working over hundreds of millions of years. Few other human endeavors engender as great a feeling of camaraderie with colleagues young and old, students and mentors alike, as making an interesting discovery together.