TY - JOUR
T1 - Psychiatric Risk Factor ANK3/Ankyrin-G Nanodomains Regulate the Structure and Function of Glutamatergic Synapses
AU - Smith, Katharine R.
AU - Kopeikina, Katherine J.
AU - Fawcett-Patel, Jessica M.
AU - Leaderbrand, Katherine
AU - Gao, Ruoqi
AU - Schürmann, Britta
AU - Myczek, Kristoffer
AU - Radulovic, Jelena
AU - Swanson, Geoffrey T.
AU - Penzes, Peter
N1 - Funding Information:
This work was supported by R01MH071316, R01MH097216 to P.P., R01NS071952 to G.T.S., R01MH078064 to J.R., and a Marie Curie Outgoing Postdoctoral Fellowship (302281) to K.R.S. We are grateful to Bryan Copits and Claire Vernon for assistance with electrophysiology, Tristan Hedrick for help with brain slicing, Vann Bennett for the goat ankyrin-G Ab, and Karen Zito, Jubao Duan, and members of the P.P. lab for helpful discussions. We thank NU Nikon Cell Imaging Facility for use of the N-SIM and spinning-disc confocal and Teng Leong Chew, Constadina Arvanitis, and Joshua Rappoport for assistance with imaging and analysis. All experiments involving animals were performed according to the Institutional Animal Care and Use Committee of NU.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/10/22
Y1 - 2014/10/22
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2014.10.010
DO - 10.1016/j.neuron.2014.10.010
M3 - Article
C2 - 25374361
AN - SCOPUS:84908223216
SN - 0896-6273
VL - 84
SP - 399
EP - 415
JO - Neuron
JF - Neuron
IS - 2
ER -