Mitogen-activated protein kinase/extracellular signal-regulated kinase activation in somatodendritic compartments: roles of action potentials, frequency, and mode of calcium entry.

Mitogen-activated protein kinase (MAPK) has been identified as a potential element in regulating excitability, long-term potentiation (LTP), and gene expression in hippocampal neurons. The objective of the present study was to determine whether the pattern and intensity of synaptic activity could differentially regulate MAPK phosphorylation via selective activation of different modes of calcium influx into CA1 pyramidal neurons. An antibody specific for the phosphorylated (active) form of MAPK was used to stain sections from hippocampal slices, which were first stimulated in vitro. LTP-inducing stimulation [theta-burst (TBS) and 100 Hz] was effective in inducing intense staining in both dendritic and somatic compartments of CA1 neurons. Phosphorylation of MAPK was also induced, however, with stimulation frequencies (3-10 Hz) not typically effective in inducing LTP. Intensity and extent of staining was better correlated with the spread of population spikes across the CA1 subfield than with frequency (above 3 Hz). Experiments using inhibitors of NMDA receptors and voltage-sensitive calcium channels (VSCCs) revealed that, although MAPK is activated after both TBS and 5 Hz stimulation, the relative contribution of calcium through L-type calcium channels differs. Blockade of NMDA receptors alone was sufficient to prevent MAPK phosphorylation in response to 5 Hz stimulation, whereas inhibitors of both NMDA receptors and VSCCs were necessary for inhibition of the TBS-induced staining. We conclude that the intensity and frequency of synaptic input to CA1 hippocampal neurons are critically involved in determining the path by which second-messenger cascades are activated to activate MAPK.