Boutonnet, M.; Noonan, J. D.; Pampaloni, N. P.; Plested, A.

At excitatory synapses, glutamate activates receptors in the postsynaptic membrane including the AMPA receptor. Usually considered to be the fastest receptor in the brain, AMPA receptors can produce millisecond synaptic potentials that mimic the timing of spikes. However, we found abundant slow AMPA responses in CA1 pyramidal cells. These slow responses show a mosaic distribution in individual cells and even in single dendrites (Pampaloni et al, 2021). A survey of the literature reveals cryptic reports of similar slow responses in cerebellum, striatum and other brain regions (Pampaloni and Plested, 2022). These striking observations open a new perspective on AMPA receptor diversity in the brain. To enable a detailed interrogation of these slow AMPA receptors in the brain, we sought to determine their molecular basis. We noted that slow AMPA is prevalent in ventral CA1 but rather sparse in dorsal hippocampus and absent in dentate gyrus granule cells. Checking published transcriptomic data, we noted that certain AMPA receptor auxiliary proteins also show gradients across these hippocampal regions. One understudied auxiliary protein identified from transcriptomics, CNIH3, produces uniquely slow AMPA responses in heterologous expression. Strikingly, we found that shRNA against CNIH3 could largely ablate slow AMPA responses in ventral CA1, and over-expression of CNIH3 in dorsal CA1 introduced very widespread slow AMPA responses. We conclude that CNIH3 is a sparsely-expressed marker of slow AMPA currents that converts individual synapses from fast followers into detonators that can spike the target cell, with wide implications for circuits, behaviour and brain pathologies.