Psychiatric Risk Factor ANK3/Ankyrin-G Nanodomains Regulate the Structure and Function of Glutamatergic Synapses

• DOI: 10.1016/j.neuron.2014.10.010
• Publication Date: 2014-10-22T15:45:24Z
• Authors: Katharine R. Smith; Katherine J. Kope...; Jessica M. Fawcet...; Katherine Leaderb...; Ruoqi Gao; Britta Schürmann; Kristoffer Myczek; Jelena Radulovic; Geoffrey T. Swanson; Peter Penzes
• Keywords: Ankyrins; Neurons; 0301 basic medicine; 03 medical and health sciences; Risk Factors; Neuroscience(all); Mutation; Synapses; Animals; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Rats

Recent evidence implicates glutamatergic synapses as key pathogenic sites in psychiatric disorders. Common and rare variants in the ANK3 gene, 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.