Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses.
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.
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA.
Katharine R
KR
Smith
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA.
Katherine J
KJ
Kopeikina
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA.
Jessica M
JM
Fawcett-Patel
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA.
Katherine
K
Leaderbrand
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA.
Ruoqi
R
Gao
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA.
Britta
B
Schürmann
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA.
Kristoffer
K
Myczek
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA.
Jelena
J
Radulovic
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA.
Geoffrey T
GT
Swanson
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA. Electronic address: p-penzes@northwestern.edu.
Peter
P
Penzes
D000818:Animals; D017487:Ankyrins / Q000737:chemistry* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012307:Risk Factors; D013569:Synapses / Q000378:metabolism*
C490614:Ank3 protein, rat; D017487:Ankyrins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate