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PolyADP-ribose-polymerase 1 is activated in neurons that mediate several forms of long-term memory in Aplysia. Because polyADP-ribosylation of nuclear proteins is a response to DNA damage in virtually all eukaryotic cells, it is surprising that activation of the polymerase occurs during learning and is required for long-term memory. We suggest that fast and transient decondensation of chromatin structure by polyADP-ribosylation enables the transcription needed to form long-term memory without strand breaks in DNA.
The formation of long-term memory requires new gene expression (1). Transcription is initiated by alteration of chromatin structure (2) induced by posttranslational modification of DNA-bound proteins through phosphorylation, acetylation, methylation, and polyADP-ribosylation (2, 3). PolyADP-ribosylation, a transient modification of nuclear proteins that regulates their binding to DNA (4-7), is catalyzed primarily by polyADP-ribose-polymerase-1 (PARP 1), a highly conserved and abundant nuclear enzyme (4-6). PolyADP-ribosylation can modify histones, transcription factors, RNA polymerase II, topoisomerases, and high-mobility group proteins (6). Activation of PARP 1 is initiated by stressful stimuli that damage DNA (6-10), but it can also be induced by other stimuli (9, 11): Depolarization of rat brain cortical neurons activates PARP 1 in the absence of DNA damage (11), which suggests that PARP 1 can be activated in neurons by physiological activity.
Does polyADP-ribosylation play a role in forming long-term memory? To answer this question, we examined two learning tasks in Aplysia. One task, governed by the pleuralpedal ganglia, is the sensitization of defensive withdrawal reflexes by noxious stimuli (1). The other, controlled by the cerebral and buccal ganglia (12), is the conditioning of feeding responses by pairing with negative reinforcing stimuli (13, 14).
A single noxious stimulus to an intact animal produces short-term sensitization of withdrawal reflexes lasting minutes; four or more spaced stimuli produce long-term sensitization lasting days to weeks (7). Sensitizing stimuli induce the release of serotonin (5-HT) from modulatory neurons. Release of the neurotransmitter that results from either short- or long-term sensitization facilitates sensory-to-motor neuron synapses in the pleural and pedal ganglia (1, 15). These synapses can also be facilitated by administering pulses of 5-HT to isolated ganglia (16). One pulse produces short-term facilitation (1, 15); five spaced pulses produce the long-term form (1, 15). To determine whether stimulation by 5-HT induces the activation of PARP 1, we...