Ubiquitin C-Terminal Hydrolase Is an Immediate-Early Gene Essential for Long-Term Facilitation in Aplysia

• Published in: Cell Vol. 89; no. 1; pp. 115 - 126
• Main Authors: Hegde, Ashok N., Inokuchi, Kaoru, Pei, Wanzheng, Casadio, Andrea, Ghirardi, Mirella, Chain, Daniel G., Martin, Kelsey C., Kandel, Eric R., Schwartz, James H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.04.1997
• Subjects: Amino Acid Sequence; Animals; Antibodies - pharmacology; Aplysia; Aplysia - physiology; Base Sequence; Blotting, Northern; Cells, Cultured - drug effects; Cells, Cultured - enzymology; Cyclic AMP - pharmacology; Cyclic AMP-Dependent Protein Kinases - metabolism; Ganglia, Invertebrate - cytology; Genes, Immediate-Early - physiology; Long-Term Potentiation - genetics; Marine; Memory - physiology; Microinjections; Molecular Sequence Data; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - immunology; Nerve Tissue Proteins - metabolism; Neurons, Afferent - drug effects; Neurons, Afferent - enzymology; Oligonucleotides, Antisense - pharmacology; Proteins - metabolism; RNA, Messenger - analysis; Serotonin - pharmacology; Substrate Specificity; Thiolester Hydrolases - genetics; Thiolester Hydrolases - immunology; Thiolester Hydrolases - metabolism; Ubiquitin Thiolesterase; Ubiquitins - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)80188-9

The switch from short-term to long-term facilitation of the synapses between sensory and motor neurons mediating gill and tail withdrawal reflexes in Aplysia requires CREB-mediated transcription and new protein synthesis. We isolated several downstream genes, one of which encodes a neuron-specific ubiquitin C-terminal hydrolase. This rapidly induced gene encodes an enzyme that associates with the proteasome and increases its proteolytic activity. This regulated proteolysis is essential for long-term facilitation. Inhibiting the expression or function of the hydrolase blocks induction of long-term but not short-term facilitation. We suggest that the enhanced proteasome activity increases degradation of substrates that normally inhibit long-term facilitation. Thus, through induction of the hydrolase and the resulting up-regulation of the ubiquitin pathway, learning recruits a regulated form of proteolysis that removes inhibitory constraints on long-term memory storage.