Dynamic regulation of calcium-permeable AMPA receptors (CP-AMPARs) is important for normal synaptic transmission, plasticity and pathological changes. Although the involvement of transmembrane AMPAR regulatory proteins (TARPs) in trafficking of calcium-impermeable AMPARs (CI-AMPARs) has been extensively studied, their role in the surface expression and function of CP-AMPARs remains unclear. We examined AMPAR-mediated currents in cerebellar stellate cells from stargazer mice, which lack the prototypical TARP stargazin (γ-2). We found a marked increase in the contribution of CP-AMPARs to synaptic responses, indicating that, unlike CI-AMPARs, these can localize at synapses in the absence of γ-2. In contrast with CP-AMPARs in extrasynaptic regions, synaptic CP-AMPARs displayed an unexpectedly low channel conductance and strong block by intracellular spermine, suggesting that they were 'TARPless'. As a proof of principle that TARP association is not an absolute requirement for AMPAR clustering at synapses, miniature excitatory postsynaptic currents mediated by TARPless AMPARs were readily detected in stargazer granule cells following knockdown of their only other TARP, γ-7.
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We thank all members of the S.G.C.-C./M.F. laboratory for invaluable discussions. We are grateful to L. Kelly and A.V. Stempel for help during the early stages of the project and to I. Coombs for assistance with molecular biology. M. Yamasaki and M. Watanabe (Hokkaido University Graduate School of Medicine) generously shared unpublished data with us. We thank G. Szabó (Institute of Experimental Medicine) for GAD65-eGFP mice, kindly provided by M. Häusser (Wolfson Institute, University College London), and M. Hastings (Medical Research Council, Laboratory of Molecular Biology) for stargazer mice. This work was supported by a Wellcome Trust Programme Grant (S.G.C.-C. and M.F.) and a Medical Research Council Programme Grant (S.G.C.-C. and M.F.). C.B. was supported by a Marie Curie Intra-European Fellowship.
The authors declare no competing financial interests.
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Bats, C., Soto, D., Studniarczyk, D. et al. Channel properties reveal differential expression of TARPed and TARPless AMPARs in stargazer neurons. Nat Neurosci 15, 853–861 (2012). https://doi.org/10.1038/nn.3107
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