Genetic and pharmacological experiments have recently implicated several protein kinase cascades in LTP and memory formation. The small GTPases of the Ras subfamily are activated by multiple extracellular stimuli and, via a complex array of downstream effectors, they control a variety of cellular events that culminate in gene transcription. In the well-characterized Aplysia gill-withdrawal reflex, activation of the Ras-dependent mitogen- activated protein kinase (MAPK) cascade is essential for the long-term, but not the short-term, facilitation process. In addition, in the rodent hippocampus, specific inhibition of the MAPK pathway significantly impairs the induction of LTP, which implicates this signalling cascade in hippocampal-dependent behaviour. Mice that lack the neuronal-specific Ras regulator, Ras-GRF (guanine-releasing factor), have severely impaired LTP in the amygdala and a corresponding deficit in long-term memory for aversive events. The results obtained from these different systems demonstrate the involvement of Ras-dependent signalling in neuronal plasticity and behaviour and raise a number of intriguing questions.
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