In addition to suggesting a species difference in the molecular mechanisms underlying synaptic plasticity, these results highlight an apparent disconnect between the mouse LTP data and the mouse contextual learning data (compare Fig. 3 with Fig. 4). Although 100-Hz LTP in the mouse hippocampus is unaffected by MEK inhibition, administration of SL327 has been shown to impair contextual fear conditioning, a learning paradigm dependent on the integrity of the hippocampus.40,78 Based on the lack of correspondence between these results, LTP induced with a pair of 100-Hz tetani does not appear to be a viable in vitro physiological model for contextual fear conditioning in the mouse.
We and others have observed that other forms of synaptic plasticity present in the mouse hippocampus are ERK-dependent and could therefore reconcile murine LTP and contextual fear learning. For example, in a recent study, Winder and colleagues demonstrated that LTP induced by theta frequency stimulation (5 Hz for 30 sec) is blocked by application of U0126 in hippocampal slices prepared from C57BL/6 mice.104 It should also be noted that similar to the present study this group observed no effect of U0126 application on LTP induced by a single 100-Hz train in these mice. Thus, the theta-frequency stimulation used in Winder et al104 may represent a more physiologically relevant LTP-induction paradigm in the mouse and may serve as a better model for hippocampus-dependent learning in this species.
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