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Mol Psychiatry. 2018 Nov 30. doi: 10.1038/s41380-018-0308-x. [Epub ahead of print]

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

Author information

1
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
2
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, 48109, USA.
3
Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong, University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
4
Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710, USA.
5
Departments of Biochemistry, Neurobiology, and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, 27710, USA.
6
Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, USA.
7
Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.
8
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
9
Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
10
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. pjenkins@umich.edu.
11
Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, USA. pjenkins@umich.edu.

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.

PMID:
30504823
DOI:
10.1038/s41380-018-0308-x

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