MAPK cascade signalling and synaptic plasticity

In mature neurons, the mitogen-activated protein kinase (MAPK) cascade that leads to the activation of extracellular signal-regulated kinases (ERKs) is stimulated by excitatory glutamatergic signalling, and might therefore have a role in synaptic plasticity.Elucidation of the roles of ERKs in the brain has been aided by the development of specific inhibitors of MAPK cascades. Inhibitors have been used to block the induction of long-term potentiation in the hippocampus. ERK-dependency has since been demonstrated for many other forms of synaptic plasticity.Experiments that used inhibitors in behaving animals have indicated that ERK is involved in learning and memory (spatial learning, fear conditioning and conditioned taste aversion).At the cellular level, ERK activity influences two processes that probably underlie changes in synaptic transmission — the activity of postsynaptic AMPA receptors, and structural plasticity.Active ERK is present in the nuclei of stimulated cells, as well as in the cytoplasm and dendrites, indicating that the ERK cascade controls phosphorylation of targets both within nuclei and close to synapses.Substrates for the ERK cascade during synaptic plasticity probably include the voltage-dependent potassium channel KV4.2, cytoskeletal proteins and transcription factors such as Elk1 and CREB.p38 MAPK is highly expressed in the adult brain. Evidence is emerging that the kinase cascade leading to the activation of this MAPK is also a key regulator of synaptic plasticity.