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The induction of long-term potentiation attenuates kainic acid-induced excitotoxicity Evans, Gary Lee

Abstract

The activation of N-methyl-D-aspartate glutamate receptors (NMDARs) is required for the long term potentiation (LTP) and long term depression (LTD) of excitatory synaptic transmission at hippocampal CA1 synapses, and plays an important role in learning and memory. In addition, it is accepted that the over-activation of NMDARs leads to the neurotoxicity associated with stroke and other neurodegenerative disorders. Thus, the NMDAR provides a logical starting point to investigate a possible relationship between synaptic plasticity and the cell-signalling pathways which ultimately determine neuronal fate. Research in our lab has indicated that NR2A-containing NMDARs are essential for LTP induction whereas NR2B-containing NMDARs are crucial for the production of LTD in vitro, and the results of this study support these findings in the anaesthetized rat. Furthermore, using the kainic acid (KA) model of neurotoxicity, this research has explored the opposing roles that activity-dependent synaptic plasticity, through different NMDAR subtypes, can play in determining neuronal outcome in an excitotoxic environment. In these experiments, it is shown that (1) the induction of LTP using high-frequency stimulation (HFS) promotes the phosphorylation of Akt, which plays a critical role in controlling cell survival and apoptosis, (2) the induction of LTP using HFS attenuates kainic acid (KA) induced neurodegeneration while the induction of LTD using low-frequency stimulation (LFS) has no incremental effect on the degree of cell death resulting from exposure to KA, (3) the blockade of NR2B-containing NMDARs using Ro25-6981 attenuates KA-induced neurodegeneration while the blockade of NR2A-containing NMDARs using NVP-AAM077 does not influence KA-induced neurotoxicity, (4) pre-treatment with NR2A antagonists blocks both the induction of LTP and its neuroprotective effect against KA while NR2B antagonists neither block the induction of LTP nor the neuroprotection that this can provide against KA, (5) the administration of NR2A antagonists after the induction of LTP has no effect on the expression of LTP or its neuroprotective effect against KA, and (6) pre-treatment with a high dose (2.4mg/kg) of NVP-AAM077 leads to the induction of LTD rather than LTP as a result of HFS. Altogether this research supports the hypothesis that the production of LTP via the activation of NR2A-containing NMDARs protects neurons against excitotoxic neuronal death by promoting cell survival signalling. Furthermore, because NR2A antagonists applied after the production of LTP do not block neuroprotection, it can be concluded that LTP itself, and not NR2A activation, is responsible for this neuroprotective effect.

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