Molecular Neurobiology Copyright 9 2000 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0893-7648/ 99 / 20(2/3): 125-142/$14.50 Ubiquitin-Mediated Proteolysis in Learning and Memory Daniel G. Chain, James H. Schwartz* and Ashok N. Hegde Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, 722 West 168th Street, New York, NY 10032 Abstract Sensitization of defensive reflexes in Aplysia is a simple behavioral paradigm for studying both short- and long-term memory. In the marine mollusk, as in other animals, memory has at least two phases: a short-term phase lasting minutes and a long-term phase lasting several days or longer. Short-term memory is produced by covalent modification of pre-existing proteins. In con- trast, long-term memory needs gene induction, synthesis of new protein, and the growth of new synapses. The switch from short-term (STF) to long-term facilitation (LTF) in Aplysia sensory neu- rons requires not only positive regulation through gene induction, but also the specific removal of several inhibitory proteins. One important inhibitory protein is the regulatory (R) subunit of the cAMP-dependent protein kinase (PKA). Degradation of R subunits, which is essential for initiat- ing long-term stable memory, occurs through the ubiquitin-proteasome pathway. Introduction Underlying the physiological changes that take place during sensitization is enhanced output of neurotransmitter (facilitation) at sen- sory-to-motor neuron synapses. Serotonin (5- HT), a major neurotransmitter released in response to sensitizing stimulation, produces the facilitation (Walters et al., 1983; Mercer et al., 1991; Emptage and Carew, 1993; Mauelshagen et al., 1996; Zhang et al., 1997). In short-term facilitation (STF), activation of adenylyl cyclase by 5-HT causes the increased output of neurotransmitter at the sensory-to- motor neuron synapses (probably glutamate; Dale and Kandel, 1993) through reversible phosphorylation of pre-existing proteins, including a K + channel (Kandel and Schwartz, 1982). In contrast, repeated stimulation induces the transcription of genes and synthe- sis of the proteins needed for an enduring increase in synaptic effectiveness (Goelet et al., 1996; Barzilai et al., 1989; Byrne et al., 1993; Byrne and Kandel, 1996). The increased output of transmitter in long- term facilitation (LTF) is brought about by a * Author to whom all correspondenceand reprint requests should be addressed. E-maihjhs6@columbia.edu Molecular Neurobiology 125 Volume 20, 1999