Psychiatric Risk FactorANK3/Ankyrin-G Nanodomains Regulate the Structure and Function of Glutamatergic Synapses

• Published in: Neuron (Cambridge, Mass.) Vol. 84; no. 2; p. 399
• Main Authors: Smith, Katharine R, Kopeikina, Katherine J, Fawcett-Patel, Jessica M, Leaderbrand, Katherine, Gao, Ruoqi, Schürmann, Britta, Myczek, Kristoffer, Radulovic, Jelena, Swanson, Geoffrey T, Penzes, Peter
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Limited 22.10.2014
• Subjects: Autism; Disease; Experiments; Health risk assessment; Information storage; Microscopy; Morphology; Neurons; Pathogenesis; Proteins; Studies
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2014.10.010

Recent evidence implicates glutamatergic synapses as key pathogenic sites in psychiatric disorders. Common and rare variants in theANK3gene, encoding ankyrin-G, have been associated with bipolar disorder, schizophrenia, and autism. Here we demonstrate that ankyrin-G is integral to AMPAR-mediated synaptic transmission and maintenance of spine morphology. Using superresolution microscopy we find that ankyrin-G forms distinct nanodomain structures within the spine head and neck. At these sites, it modulates mushroom spine structure and function, probably as a perisynaptic scaffold and barrier within the spine neck. Neuronal activity promotes ankyrin-G accumulation in distinct spine subdomains, where it differentially regulates NMDA receptor-dependent plasticity. These data implicate subsynaptic nanodomains containing a major psychiatric risk molecule, ankyrin-G, as having location-specific functions and open directions for basic and translational investigation of psychiatric risk molecules.