Regulation of synaptic plasticity by the cyclic-AMP signalling pathway.

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Learning is the acquisition of new knowledge about the environment, and memory is its retention over time. Much of what we do in the present and future is shaped by what we remember from our past experiences. A major goal of neurobiology is to identify the complex molecular and cellular mechanisms that importantly regulate learning and memory storage in the mammalian brain. Activity-dependent changes in synaptic strength ("synaptic plasticity") are critical for specific forms of learning and memory. Long-term potentiation (LTP) is an activity-induced enhancement of the physiological strength of excitatory synapses widely regarded as a synaptic mechanism for memory. Many of the molecular mechanisms required for LTP to be maintained are also critical for memory function. As such, elucidating the molecular mechanisms that are critical for LTP continues to shed light on the mechanisms of memory storage, and may reveal viable strategies for improving mental health. Numerous signaling pathways have been implicated in both LTP and memory storage in the mammalian hippocampus, a brain structure critical for making new long-term memories. One pathway that is critical for memory storage and synaptic plasticity in a wide range of animal species (from flies and snails to mice) is the cyclic-AMP (cAMP) signaling pathway. This consists mainly of cAMP, cAMP-dependent protein kinase (PKA), and "exchange protein activated by cAMP" (Epac). PKA and Epac are proteins that bind cAMP and are activated by it. PKA is anchored to specific intracellular loci by A-kinase anchoring proteins (AKAPs). Their ability to spatially restrict PKA's effects to specific subcellular compartments of neurons makes them an important determinant of where cAMP signaling can have substantial impact within neurons. Noradrenaline regulates crucial brain functions such as learning, memory, sleep, and attention. Elucidating how noradrenaline impacts synaptic signaling may reveal treatments for memory impairment, PTSD, and other disorders linked to abnormal noradrenergic physiology. My lab has pioneered the identification of PKA, Epac, and AKAPs as key players in modulating LTP following activation of noradrenergic receptors. We will use newly available pharmacological agents that disrupt the functions of specific isoforms of AKAPs and Epac to assess their roles in regulating expression of LTP. These studies will pioneer this area of research by identifying the roles of Epac and AKAPs in synaptic plasticity. Understanding how the brain forms and stores memories is an important milestone that will help elucidate the neural mechanisms of other cognitive processes, such as perception, attention, and "consciousness", that are intimately intertwined with memory processing.