The influence of glutamate receptor 2 expression on excitotoxicity in GluR2 null mutant mice

AMPA receptor (AMPAR)-mediated ionic currents that govern gene expression, synaptic strength, and plasticity also can trigger excitotoxicity. However, native AMPARs exhibit heterogeneous pharmacological, biochemical, and ioni c permeability characteristics, which are governed partly by receptor subun it composition. Consequently, the mechanisms governing AMPAR-mediated excit otoxicity have been difficult to elucidate. The GluR2 subunit is of particu lar interest because it influences AMPAR pharmacology, Ca2+ permeability, a nd AMPAR interactions with intracellular proteins. In this paper we used mu tant mice lacking the AMPAR subunit GluR2 to study AMPAR-mediated excitotox icity in cultured cortical neurons and in hippocampal neurons in vivo. We e xamined the hypothesis that in these mice the level of GluR2 expression gov erns the vulnerability of neurons to excitotoxicity and further examined th e ionic mechanisms that are involved. In cortical neuronal cultures AMPAR-m ediated neurotoxicity paralleled the magnitude of kainate-evoked AMPAR-medi ated currents, which were increased in neurons lacking GluR2. Ca2+ permeabi lity, although elevated in GluR2-deficient neurons, did not correlate with excitotoxicity. However, toxicity was reduced by removal of extracellular N a+, the main charge carrier of AMPAR-mediated currents. In vivo, the vulner ability of CA1 hippocampal neurons to stereotactic kainate injections and o f CA3 neurons to intraperitoneal kainate administration was independent of GluR2 level. Neurons lacking the GluR2 subunit did not demonstrate compensa tory changes in the distribution, expression, or function of AMPARs or of C a2+-buffering proteins. Thus GluR2 level may influence excitotoxicity by ef fects additional to those on Ca2+ permeability, such as effects on agonist potency, ionic currents, and synaptic reorganization.