TY - JOUR T1 - Proteasomal-mediated degradation of AKAP150 accompanies AMPAR endocytosis during cLTD JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0218-19.2020 SP - ENEURO.0218-19.2020 AU - Wenwen Cheng AU - Dolores Siedlecki-Wullich AU - Judit Català-Solsona AU - Cristina Fábregas AU - Rut Fadó AU - Núria Casals AU - Montse Solé AU - Mercedes Unzeta AU - Carlos A Saura AU - José Rodríguez-Alvarez AU - Alfredo J. Miñano-Molina Y1 - 2020/03/16 UR - http://www.eneuro.org/content/early/2020/03/16/ENEURO.0218-19.2020.abstract N2 - The number and function of synaptic AMPA receptors (AMPARs) tightly regulates excitatory synaptic transmission. Current evidence suggests that AMPARs are inserted into the postsynaptic membrane during long-term potentiation (LTP) and are removed from the membrane during long-term depression (LTD). Dephosphorylation of GluA1 at Ser845 and enhanced endocytosis are critical events in the modulation of LTD. Moreover, changes in scaffold proteins from the postsynaptic density (PSD) could be also related to AMPAR regulation in LTD. In the present study we analyzed the effect of chemical LTD (cLTD) on A-kinase anchoring protein (AKAP) 150 and AMPARs levels in mouse-cultured neurons. We show that cLTD induces AKAP150 protein degradation via proteasome, coinciding with GluA1 dephosphorylation at Ser-845 and endocytosis of GluA1-containing AMPARs. Pharmacological inhibition of proteasome activity, but not phosphatase calcineurin (CaN), reverted cLTD-induced AKAP150 protein degradation. Importantly, AKAP150 silencing induced dephosphorylation of GluA1 Ser-845 and GluA1-AMPARs endocytosis while AKAP150 overexpression blocked cLTD-mediated GluA1-AMPARs endocytosis. Our results provide direct evidence that cLTD-induced AKAP150 degradation by the proteasome contributes to synaptic AMPARs endocytosis.Significance Statement Multiple evidences have shown that changes in glutamatergic synaptic AMPA receptors (AMPARs) modulate excitatory synaptic plasticity, playing a fundamental role in learning and memory-related processes such as long-term potentiation (LTP) or long-term depression (LTD). AMPARs are inserted in the synapses during LTP and removed during LTD although the mechanisms involved in synaptic AMPARs dynamics are not fully understood. Here, we show that cLTD-dependent proteasome degradation of A-kinase anchoring protein (AKAP) 150, a scaffold protein from the postsynaptic density, is related to synaptic AMPARs removal during cLTD whereas restored AKAP150 levels blocks cLTD-mediated endocytosis of AMPARs. Thus, our findings expand our understanding of the regulatory role of AKAP150 on AMPARs dynamics at glutamatergic synapses. ER -