21 Jun 2004

When a cell responds to stress or DNA damage, a variety of nuclear proteins undergo PolyADP-ribosylation. Beyond that, however, the requisite enzyme—polyADP-ribose polymerase I, or PARP 1—is activated also in unstressed neurons that are storing memories. Reported in the June 18 Science by James Schwartz and colleagues at Columbia University, New York, and Tel-Aviv University, Israel, the results suggest that there’s more to ADP-ribosylation than just DNA repair.

A few years ago, it was shown that PARP can be activated in rat cortical neurons by depolarization events, even in the absence of DNA damage (Homburg et al., 2000). This made Schwartz and colleagues wonder if PARP may be involved in forming memories. To test this, first author Malka Cohen-Armon exposed neurons of the sea slug Aplysia to 5-hydroxytryptamine (5-HT), otherwise known as serotonin, a neurotransmitter that is indispensable in mammalian brains. In pleural pedal ganglia of Aplysia, serotonin mimics noxious stimuli, and controlled administration of the chemical has the same effect as exposure to such stimulation—the animal learns to withdraw from the source. One pulse of serotonin leads to a short-term improvement in the animal’s reflexes, while five pulses lead to long-term improvement, suggesting the animal has “learned” to respond to noxious stimulation.

When the authors examined neurons stimulated by 5-HT, they found that one pulse had little effect on PARP; five pulses, however, converted some of the enzyme to a more acidic form. It is known that PARP ADP-ribosylates itself, consistent with acidification, and indeed an inhibitor of PARP, 3-aminobenzamide (3-AB), prevented the induction of the acidic form. The results suggested the enzyme was modified while the long-term memory was being formed.

But is activation of PARP a cause or effect of memory formation? To approach this question, the authors first trained the animals to respond to food they cannot swallow. Under these conditions the slugs learn that the food is unpalatable and their feeding response decreases. This is accompanied by acidification of PARP. When Cohen-Armon first gave the animals the PARP inhibitor, they did not learn that the food was inedible and failed to decrease their feeding response. In short, they couldn’t learn to distinguish good food from bad.

It is not known whether PARP-1 has similar effects in mammals. Given that DNA damage may play a role in neurodegenerative disease (see ARF related news story) and that PARP-1 is involved in DNA repair, its involvement in long-term memory would make it doubly interesting.—Tom Fagan