NMDA Receptor-Dependent LTD Requires Transient Synaptic Incorporation of Ca2+-Permeable AMPARs Mediated by AKAP150-Anchored PKA and Calcineurin

• Published in: Neuron (Cambridge, Mass.) Mass.), 2016-03, Vol.89 (5), p.1000-1015
• Main Authors: Sanderson, Jennifer L., Gorski, Jessica A., Dell’Acqua, Mark L.
• Format: Article
• Language: English
• Subjects: A Kinase Anchor Proteins - genetics; A Kinase Anchor Proteins - metabolism; Animals; Calcineurin - genetics; Calcineurin - metabolism; Calcium - metabolism; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Electric Stimulation; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Agents - pharmacology; Hippocampus - cytology; Hippocampus - ultrastructure; Kinases; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - genetics; Long-Term Synaptic Depression - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Molecular; Mutation - genetics; Phosphatase; Phosphorylation; Proteins; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Recruitment; Rodents; Silver Staining; Studies; Synapses - genetics; Synapses - physiology; Synapses - ultrastructure; Synaptic Potentials - drug effects; Synaptic Potentials - genetics
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2016.01.043

Information processing in the brain requires multiple forms of synaptic plasticity that converge on regulation of NMDA and AMPA-type glutamate receptors (NMDAR, AMPAR), including long-term potentiation (LTP) and long-term depression (LTD) and homeostatic scaling. In some cases, LTP and homeostatic plasticity regulate synaptic AMPAR subunit composition to increase the contribution of Ca2+-permeable receptors (CP-AMPARs) containing GluA1 but lacking GluA2 subunits. Here, we show that PKA anchored to the scaffold protein AKAP150 regulates GluA1 phosphorylation and plays a novel role controlling CP-AMPAR synaptic incorporation during NMDAR-dependent LTD. Using knockin mice that are deficient in AKAP-anchoring of either PKA or the opposing phosphatase calcineurin, we found that CP-AMPARs are recruited to hippocampal synapses by anchored PKA during LTD induction but are then rapidly removed by anchored calcineurin. Importantly, blocking CP-AMPAR recruitment, removal, or activity interferes with LTD. Thus, CP-AMPAR synaptic recruitment is required to transiently augment NMDAR Ca2+ signaling during LTD induction. •AKAP150-PKA promotes GluA1 phosphorylation and CP-AMPAR synaptic recruitment in LTP•AKAP150-PKA signaling also recruits CP-AMPARs to synapses during LTD induction•AKAP150-calcineurin signaling rapidly removes CP-AMPARs recruited during LTD•CP-AMPAR recruitment confers a transient meta-plastic state that promotes LTD Sanderson et al. reveal a novel requirement for signaling by Ca2+-permeable AMPA receptors during induction of long-lasting synaptic depression and show that these receptors are transiently recruited to synapses by phosphorylation/dephosphorylation that is coordinated by the kinase/phosphatase scaffold protein AKAP150.