LTP requires a reserve pool of glutamate receptors independent of subunit type

Long-term potentiation (LTP) of synaptic transmission is thought to be a key cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic tail of the AMPA receptor subunit GluA1. To find the minimum necessary requirement of the GluA1 C-tail for LTP in CA1 hippocampal pyramidal neurons, we used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors with transfected subunits. In striking contrast to the prevailing model, we found no requirement of the GluA1 C-tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with dramatically decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. These results demonstrate the synapse’s remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in our thinking with regard to the core molecular events underlying synaptic plasticity.