GluA2-lacking AMPA receptors in hippocampal CA1 cell synapses: evidence from gene-targeted mice

The GluA2 subunit in heteromeric alpha−amino−3−hydroxy−5−methyl−4−isoxazolepropionic acid (AMPA) receptor channels restricts Ca2+ permeability and block by polyamines, rendering linear the current−voltage relationship of these glutamate−gated cation channels. Although GluA2−lacking synaptic AMPA receptors occur in GABA−ergic inhibitory neurons, hippocampal CA1 pyramidal cell synapses are widely held to feature only GluA2 containing AMPA receptors. A controversy has arisen from reports of GluA2−lacking AMPA receptors at hippocampal CA3−to−CA1 cell synapses and a study contesting these findings. Here we sought independent evidence for the presence of GluA2−lacking AMPA receptors in CA1 pyramidal cell synapses by probing the sensitivity of their gated cation channels in wild−type (WT) mice and gene−targeted mouse mutants to philanthotoxin, a specific blocker of GluA2−lacking AMPA receptors. The mutants either lacked GluA2 for maximal philanthotoxin sensitivity, or, for minimal sensitivity, expressed GluA1 solely in a Q/R site−edited version or not at all. Our comparative electrophysiological analyses provide incontrovertible evidence for the presence in wild−type CA1 pyramidal cell synapses of GluA2−less AMPA receptor channels. This article is part of a Special Issue entitled "Calcium permeable AMPARs in synaptic plasticity and disease.