TARP γ-7 selectively enhances synaptic expression of calcium-permeable AMPARs

Regulation of calcium-permeable AMPA receptors (CP-AMPARs) is critical in normal synaptic function and neurological disease states. While transmembrane AMPAR regulatory proteins (TARPs) such as stargazin (γ-2) modulate the properties of calcium-impermeable (CI-) AMPARs and promote their synaptic targeting, the TARP-specific rules governing CP-AMPAR synaptic trafficking remain unclear. We used RNA interference to manipulate AMPAR subunit- and TARP expression in γ-2-lacking stargazer cerebellar granule cells – the classic model of TARP deficiency. We found that TARP γ-7 selectively enhanced synaptic expression of CP-AMPARs and suppressed CI-AMPARs, identifying a pivotal role of γ-7 in regulating the prevalence of CP-AMPARs. In the absence of associated TARPs, although their properties were altered, both CP- and CI-AMPARs were able to localize at synapses and mediate transmission. Finally, our results establish that TARPed synaptic receptors in granule cells require both γ-2 and γ-7, and reveal an unexpected basis for the loss of AMPAR-mediated transmission in stargazer mice.