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John H Byrne “Neural and Molecular Mechanisms for Elementary Forms of Short- and Long-Term Memories”

Abstract :

Defensive withdrawal reflexes of the mollusk Aplysia have been widely used as model systems for studying the short- and long-lasting forms of sensitization, a simple form of nonassociative learning. Serotonin (5-HT) plays a critical role in the induction of sensitization and the biochemical and electrophysiological processes, which support sensitization have been well characterized.
The somata and processes of the sensory neurons are richly innervated by serotonin-containing processes and sensitizing stimuli lead to the release of serotonin. Serotonin engages at least three types of receptors on the sensory neurons; one coupled to the cyclic AMP protein kinase A (PKA) system, another coupled to the diacylglycerol protein kinase C (PKC) system, and a third coupled to the MAPK cascade. The PKA and PKC systems affect both the electrophysiological and biochemical properties of the cell and mediate short-term sensitization. Long-term sensitization, like short-term sensitization, is correlated with electrophysiological changes, and changes in transmitter release in sensory neurons, which persist for at least 24 hours. However, the long-term changes are also associated with growth of neuronal processes. These effects can be mimicked by application of 5-HT. They are also dependent on new protein synthesis and many of the genes involved in the induction and maintenance of long-term facilitation have been identified. One protein whose synthesis is regulated is Aplysia tolloid/BMP-like protein (ApTBL–1). Tolloid and the related molecule BMP–1 appear to function as secreted Zn2+ proteases where they activate members of the transforming growth factor β (TGF-β) family. Indeed, in sensory neurons, TGF-β mimics the effects of 5-HT in that it produces long-term increases in synaptic strength of the sensory neurons. Interestingly, TGF-β activates MAPK in the sensory neurons and induces its translocation to the nucleus. Thus, TGF-β could be part of an extracellular positive feedback loop possibly leading to another round of protein synthesis to further consolidate the memory. A second important protein is CREB1, which shows a CRE-dependent increase in expression with LTF. The combination of its
increased expression post induction and its persistent phosphorylation closes an intracellular positive feedback loop that is necessary for memory consolidation. The time course of the requirement for CREB1 synthesis in the consolidation of long-term memory was examined using RNAi techniques in sensorimotor cocultures. The results demonstrate that CREB1 must be sustained for a relatively long time in order to support consolidation of LTF. In addition, LTF is also accompanied by a long-term increase in the excitability (LTE) of the sensory neurons. Because LTE was observed in isolated sensory neurons, this long-term change was intrinsic to sensory neurons. LTE was blocked when CREB1 siRNA was injected into isolated sensory neurons immediately after 5-HT treatment. These data suggest that the CREB1 synthesis is required for consolidation of both LTF and LTE. 

Selected publications

Antzoulatos, E.G. and Byrne, J.H. Long-term sensitization training produces spike narrowing in Aplysia sensory neurons. J. Neuroscience, 27:676-683, 2007.
Liu, R.Y., Fioravante, D., Shah, S. and Byrne, J.H. cAMP response element-binding protein 1 feedback loop is necessary for consolidation of long-term synaptic facilitation in Aplysia. J. Neuroscience, 28: 1970-1976, 2008.

Mozzachiodi, R. and Byrne, J.H. More than synaptic plasticity: Role of nonsynaptic plasticity in learning and memory. Trends in Neurosciences 33:17-26, 2010.

Romuald Nargeot