Regulation of Extracellular Signal-Regulated Kinase during Long-term Potentation in area CA1 of the Rat Hippocampus in vivo

The extracellular signal-regulated kinase (ERK) cascade can transduce cell-surface signals to the nucleus in post-synaptic neurons during hippocampus-dependent learning and hippocampus-dependent synaptic plasticity, yet, whether the cascade can convey information about stimulus frequency or synaptic modification direction to the nucleus during plasticity events has not been addressed. The objective of the current study was to investigate whether ERK regulation differs as a function of stimulus frequency and in accordance with synaptic modification direction by comparing ERK regulation during LTP in area CA1 of the hippocampus in vivo to previous findings for ERK regulation during LTD in area CA1 in vivo (Thiels et al., 2002). The ultimate goal was to determine whether ERK functions as a general or as a specific plasticity kinase during synaptic plasticity events in the hippocampus. Using a combination of in vivo electrophysiology, pharmacology and Western blot analysis, I demonstrate that: (1) LTP induced by high-frequency stimulation applied to commissural fiber inputs to area CA1 pyramidal cells in the adult hippocampus in vivo is accompanied by a rapid yet transient increase in ERK2 activation; (2) blockade of NMDA receptors by MK-801 blocks both LTP induction and the associated increase in ERK2 activation; (3) HFS delivered in the presence of the ERK kinase inhibitor SL327 fails to produce a persistent potentiation; (5) phosphorylation of the transcriptional regulator cAMP response element-binding protein (CREB) is increased after HFS; and (6) inhibition of ERK activation by SL327 blocks this observed increase in pCREB. The similarity of the current findings with previous findings for ERK2 activation and regulation during LTD in area CA1 in vivo, suggests that the ERK cascade conveys a general as opposed to iv a specific plasticity signal during these two forms of synaptic plasticity in area CA1 in vivo. Differences in the coupling of ERK2 activation to CREB phosphorylation between LTP and LTD (Thiels et al., 2002), suggest that other signaling cascades are most likely operative in determining the direction of synaptic modification during bidirectional synaptic plasticity in the hippocampus.