Abstract
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.”
Highlights
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels mediate most of the fast synaptic excitatory transmission in the brain
We compared the effect of PhTx-433 on EPSCs evoked in CA1 pyramidal cell synapses in hippocampal slices of GluA2−/− mice in two distinct experimental conditions, one ensuring chelation of intracellular polyamines and the other having buffered spermine added to the intracellular solution
This should be useful for revealing their existence and estimating their contribution in WT, in which they would coexist with GluA2-containing AMPARs
Summary
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels mediate most of the fast synaptic excitatory transmission in the brain. Their subunit composition determines their biophysical properties, including channel gating and ion conductance. In synaptic AMPA channels, sensitivity to endogenous polyamines and the degree of rectification can be lessened by interaction with TARPs, the transmembrane AMPAR regulatory proteins (Soto et al, 2007). As gleaned from the properties of AMPA receptors in different neuronal populations, the current consensus would state that principal excitatory neurons operate with GluA2-containing AMPA receptors (Adesnik and Nicoll, 2007; Lu et al, 2009), whereas GABA-ergic inhibitory neurons often feature GluA2-lacking synaptic AMPA receptors (Geiger et al, 1995; Toth and McBain, 1998; Liu and Cull-Candy, 2002)
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