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Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP

A Correction to this article was published on 31 January 2019

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Abstract

GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize cell surface GABAA receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.

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Data availability

Atomic coordinates and structure factors are available from the Protein Data Bank under accession code PDB 6A9X (AnkG:GABARAP).

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Acknowledgements

We thank the Shanghai Radiation Facility BL19U1 and BL17U1 for X-ray beam time. Funding for this work was provided by the Michigan Predoctoral Training in Genetics (T32GM007544) (ADN), NIH Early Stage Training in the Neurosciences Training Grant (T32NS076401) (JCRD and JMH), Heinz C. Prechter Bipolar Research program and Richard Tam Foundation, University of Michigan Depression Center (PMJ), R37NS076752 (LLI), National Natural Science Foundation of China (NSFC 31670734) (CW), Research Grants Council of Hong Kong (16100517 and AoE-M09-12) (MZ), R01DA020140 (KSJ), and the Howard Hughes Medical Institute (VB). Finally, we thank Dr. Ed Cooper (Baylor College of Medicine) for providing the KCNQ2N1 antibody.

Author contributions

ADN, RNFC, CW, MZ, KSJ, LLS, LLI, and PMJ designed research. PMJ, KKW, KC, and VB generated and initially characterized the Ank3 W1989R mutant mice. ADN, RNCF, JCRD, JMH, YY, JL, KC, and CW performed experiments. ADN, RNCF, JCRD, CW, MZ, KSJ, and PMJ analyzed data. MMG provided human samples and clinical diagnosis. ADN and PMJ wrote the manuscript.

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Correspondence to P. M. Jenkins.

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Nelson, A.D., Caballero-Florán, R.N., Rodríguez Díaz, J.C. et al. Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP. Mol Psychiatry 25, 2800–2817 (2020). https://doi.org/10.1038/s41380-018-0308-x

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