ERK in Hippocampal Synaptic Plasticity

Considerable evidence already exists implicating ERK in various forms of synaptic plasticity in a wide variety of systems. Long-term facilitation of the sensory-motor neuron synapse in Aplysia causes translocation of ERK into the nucleus of presynaptic neurons. Furthermore, inhibition of ERK by either anti-MAPK antibodies or PD098059 blocks long-term, but not short-term, facilitation of the sensory-motor synapse.67,72 ERK has also been shown to be activated during an in vitro Pavlovian conditioning paradigm in Hermissenda, and this activation is blocked by pretreatment with PD098059. Activation of the ERK isoforms of MAPK have been demonstrated to be necessary for the induction of NMDA receptor-dependent LTP in area CA1 of the rat hippocampus (see Fig. 3)'8'37'38'51'52'104'105 NMDA receptor-independent LTP in area in the dentate gyrus, ' LTP in vivo,3 , and LTP of the amygdalar inputs into the insular cortex.55 In addition, long-term depression (LTD) in the rat hippocampus is associated with long-lasting decreases in ERK immunoreactivity.76

Surprisingly, inhibiting ERK activation produced differential effects, depending on the species, on hippocampal long-term potentiation induced with a high-frequency stimulation (HFS) paradigm consisting of two trains of 1-sec, 100-Hz tetani (Fig. 3). In vehicle-treated hippoc-

Hippocampus Ltp Stimulationg

Figure 3. HFS-LTP requires ERK activation in rat but not mouse hippocampus. A) LTP induced with a pair of 100-Hz tetani in rat hippocampal slices in the presence of either vehicle (0.1% DMSO; n = 10 slices), 10 |M SL327 (n = 7), or 20 |M U0126 (n = 5). Inset, representative traces from vehicle- and SL327-treated rat slices before (gray) and after (black) tetanic stimulation. Scale bars are 0.5 mV by 8 msec. B) Mouse hippocampal slices exposed to the same LTP-induction paradign in the presence of either vehicle (n = 19), 10 |M SL327 (n = 11), or 20 |M U0126 (n = 10). Inset, representative traces from vehicle- and SL327-treated mouse slices before (gray) and after (black) tetanization. Scale bars are 1 mV by 8 msec.

Figure 3. HFS-LTP requires ERK activation in rat but not mouse hippocampus. A) LTP induced with a pair of 100-Hz tetani in rat hippocampal slices in the presence of either vehicle (0.1% DMSO; n = 10 slices), 10 |M SL327 (n = 7), or 20 |M U0126 (n = 5). Inset, representative traces from vehicle- and SL327-treated rat slices before (gray) and after (black) tetanic stimulation. Scale bars are 0.5 mV by 8 msec. B) Mouse hippocampal slices exposed to the same LTP-induction paradign in the presence of either vehicle (n = 19), 10 |M SL327 (n = 11), or 20 |M U0126 (n = 10). Inset, representative traces from vehicle- and SL327-treated mouse slices before (gray) and after (black) tetanization. Scale bars are 1 mV by 8 msec.

ampal slices from rats, HFS resulted in a significant and stable increase in the initial slope of the EPSP. Consistent with results obtained previously in a number of studies, this enhancement in synaptic strength was blocked by application of either 10 |M SL327 or 20 |M U0126.8,38,105 In the mouse hippocampus, however, MEK inhibitors had no effect on LTP induced with this high-frequency tetanic stimulation. These findings suggest that LTP induced with a pair of 100-Hz tetani requires ERK activation in rats but not in mice. This would then suggest the novel idea that these two closely related species do not employ identical molecular mechanisms for the induction of this particular form of synaptic plasticity.

Mice are notoriously variable depending on their particular genetic background strain. To ensure that our observation is due to a species difference as opposed to a quirk of a particular mouse strain, the LTP experiments were conducted with hippocampi from three different mouse strains: the widely used C57BL/6J strain, another inbred strain 129S1/SvImJ, and an outbred strain CD-1. The CD-1 mice serve as a simple control for their outbred counterpart, the Sprague-Dawley rat. MEK inhibitors failed to impair LTP in hippocampal slices from all three of these mouse strains, suggesting that this is not merely a strain or inbreeding effect (data not shown).

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