LY404187, a potentiator of AMPARs, enhances both the amplitude and 1/CV2 of AMPA EPSCs but not NMDA EPSCs at CA3–CA1 synapses in the hippocampus of neonatal rats

Abstract

Cyclothiazide is a well-known AMPAR potentiator, but it has also been shown to enhance the probability of presynaptic release in some cases. Interestingly, cyclothiazide has been shown to reveal AMPA EPSCs at silent CA3–CA1 synapses (which exhibit NMDA EPSCs but not AMPA EPSCs) in the hippocampus of neonatal or developing rats [5,9], but this particular result has not been reproduced at other types of synapses [12,14]. Although this discrepancy may be due to the different mechanisms underlying silent synapses in distinct brain subregions, it is also possible that cyclothiazide has pre- and postsynaptic molecular targets that are differentially expressed at the different types (or different developing stages) of synapses. In this study, we reexamined, using a new AMPAR potentiator, LY404187, whether AMPAR potentiation leads to the conversion of silent CA3–CA1 synapses into functional synapses (exhibiting both AMPA and NMDA EPSCs) in the hippocampus of neonatal rats. LY404187 did not appear to alter the probability of presynaptic release, as evidenced by the lack of significant changes in both the amplitude and the paired-pulse facilitation ratio (an index of release probability) of NMDA EPSCs. LY404187 enhanced both the amplitude and 1/CV2 (CV: coefficient of variation) of AMPA EPSCs but not NMDA EPSCs. Because an increase in 1/CV2 reflects an increased number of functional synapses and/or an enhanced release probability, the LY404187-induced increase in the 1/CV2 value of AMPA EPSCs, but not NMDA EPSCs, likely indicates an increased number of synapses exhibiting AMPA EPSCs but not an increased number of synapses exhibiting NMDA EPSCs. Because AMPARs and NMDARs are co-localized at the same synapses, our findings are consistent with a scenario in which LY404187 enables silent synapses to acquire AMPA EPSCs.