A Nobel's Life - Eric Kandel and the Aplysia

Yesterday's blog piece focused on how a young refugee from Nazi Austria studied Freud as a means of coming to terms with the brutality of man, only to get apparently sidetracked into neurobiology. Oddly enough, it turned out he was on the right course, with a very strange lab partner ...

Following a brief stint at Harvard as a staff psychiatrist, Dr Kandel joined NYU in 1965 to start a new neurophysiology group devoted to the neurobiology of behavior. In France, Dr Kandel had discovered that chemical synapses are remarkably plastic, but had yet to establish that these changes occur when an animal learns something. But how can you tell when a snail - in this case the California sea snail (aplysia, pictured here) has learned something? One giveaway is that snails reflexively withdraw their gills in response to stimuli administered to the animal’s spout (siphon), an action similar to removing one’s hand from a hot object.

As with higher animals, practice makes perfect; repeated stimuli convert short-term memory to long-term memory. The team focused initially on sensitization, a form of learned fear. A person sensitized to the sound of gunfire, for instance, may become startled by a mere tap on the shoulder. A snail sensitized to stimuli to the siphon would also respond to stimuli to the tail. The conversion of short-term memory to long-term memory resulted in the synthesis of new proteins.

The team located and mapped the neural circuit in the gill-withdrawal reflex. To the researchers’ surprise, the cells and their interconnections were always the same. What changed in the learning process were changes in synaptic strength. The cell circuits may have been hardwired, but the effectiveness of their signaling could be altered by experience. These findings led to a series of ground-breaking articles published in Science in 1970.

In 1974, Dr Kandel moved to Columbia as the founding director of the Center for Neurobiology and Behavior (and later as senior investigator of the Howard Hughes Medical Institute which has a site located there). There, he and his colleagues (many recruited from his NYU group) zeroed in on the fine points of synaptic change. This involves serotonin and other neurotransmitters acting on specific receptors located on presynaptic neurons.

The serotonin, Dr Kandel found, increases a "second messenger" molecule, cAMP, inside the neuron that sets in train the sensitization required to form short-term memory. Collaboration with Paul Greengard PhD, who would share the same stage in Stockholm with Dr Kandel, implicated the enzyme PKA in the process, along with a potassium channel regulated by PKA. Reducing the potassium current has the effect of ramping up calcium, which sends neurotransmitters on their merry little ways.

By now Dr Kandel and his team had perfected the art of experimenting on cell cultures grown from the larvae of their snails - in this case just two cells, a sensory neuron and a motor neuron. All the researchers had to do to simulate the tail stimulus effect of the snail was to "puff" micro units of serotonin into the culture. This was about as reductionist as even Dr Kandel could get.

This time Dr Kandel and his colleagues were hot on the trail of long-term memory. Repeated administration of serotonin, they found, activates PKA inside the cell. In response, PKA translocates to the nucleus where it recruits another enzyme called MAP kinase. Both kinases act on a gene regulator called CREB-1, which triggers the synthesis of new proteins (CREB) needed for the growth of new synaptic connections vital to long-term memory.

These and other findings were gradually revealed over a steady stream of articles spanning into this millennium. In his relentless investigation into the learned reflex of a simple sea creature, Dr Kandel had helped crack open the secrets of the neuron, including the discovery of a two-way dialogue between the nucleus and synapse. Neuroscience and psychiatry would never be the same. His marine lab partner, in the process, gained new respect, becoming to neurobiology what fruit flies are to genetics and rats are to behavior.

To be continued ...