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Lithium rescues dendritic abnormalities in Ank3 deficiency models through the synergic effects of GSK3β and cyclic AMP signaling pathways

Neuropsychopharmacology volume 48, pages 1000–1010 (2023)Cite this article

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Abstract

Bipolar disorder (BD) is a highly heritable mood disorder with intermittent episodes of mania and depression. Lithium is the first-in-line medication to treat BD, but it is only effective in a subset of individuals. Large-scale human genomic studies have repeatedly linked the ANK3 gene (encoding ankyrin-G, AnkG) to BD. Ank3 knockout mouse models mimic BD behavioral features and respond positively to lithium treatment. We investigated cellular phenotypes associated with BD, including dendritic arborization of pyramidal neurons and spine morphology in two models: (1) a conditional knockout mouse model which disrupts Ank3 expression in adult forebrain pyramidal neurons, and (2) an AnkG knockdown model in cortical neuron cultures. We observed a decrease in dendrite complexity and a reduction of dendritic spine number in both models, reminiscent of reports in BD. We showed that lithium treatment corrected dendrite and spine deficits in vitro and in vivo. We targeted two signaling pathways known to be affected by lithium using a highly selective GSK3β inhibitor (CHIR99021) and an adenylate cyclase activator (forskolin). In our cortical neuron culture model, CHIR99021 rescues the spine morphology defects caused by AnkG knockdown, whereas forskolin rescued the dendrite complexity deficit. Interestingly, a synergistic action of both drugs was required to rescue dendrite and spine density defects in AnkG knockdown neurons. Altogether, our results suggest that dendritic abnormalities observed in loss of function ANK3 variants and BD patients may be rescued by lithium treatment. Additionally, drugs selectively targeting GSK3β and cAMP pathways could be beneficial in BD.

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Fig. 1: AnkG maintains dendritic spine density and dendrite complexity in pyramidal neurons in vivo and in vitro.
Fig. 2: Chronic lithium treatment rescues dendrite and spine deficits in AnkG–deficient neurons in Ank3 cKO mice.
Fig. 3: Lithium treatment rescues the spine and dendrite deficits in AnkG knockdown neurons.
Fig. 4: CHHIR99021 treatment rescues only spine deficits in AnkG knockdown neurons.
Fig. 5: Forskolin treatment rescues only dendrite deficit and synergizes with CHIR99021 to rescue spine deficits in AnkG knockdown neurons.
Fig. 6: Inhibition of PKA and expression of GSK3βS9A prevent the lithium rescue in AnkG knockdown neurons.

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Acknowledgements

This work was supported by NIH R01MH107182 to PP. We thank Mrs. Lili Hamedi for her generous support. Floxed Ank3 mice were generously provided by Prof. Van Bennett from Duke University. Wide-field microscope imaging work was performed at the Northwestern University Center for Advanced Microscopy, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Metal analysis was performed at the Northwestern University Quantitative Bio-element Imaging Center generously supported by NASA Ames Research Center NNA06CB93G. We are grateful to members of the Penzes lab for helpful discussions, especially Dr. Marc P. Forrest, Dr. Marc Dos Santos, and Dr. Euan Parnell for their help on the manuscript. All experiments involving animals were performed according to the Institutional Animal Care and Use Committee of NU.

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Authors and Affiliations

  1. Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Nicolas H. Piguel, Sehyoun Yoon, Katherine E. Horan & Peter Penzes

  2. University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA

    Ruoqi Gao

  3. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jacob C. Garza & Tracey L. Petryshen

  4. Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA

    Katharine R. Smith

  5. Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Peter Penzes

  6. Northwestern University, Center for Autism and Neurodevelopment, Chicago, IL, 60611, USA

    Peter Penzes

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Contributions

NHP performed and analyzed cellular, confocal imaging and Golgi staining imaging, and led the project. SY performed conditional knockout mouse breeding and Golgi staining studies. RG and KEH generated and maintained neuronal cultures. JCG and TLP advised on the project. KRS performed cellular experiments. PP supervised the project. NHP, SY, JCG, TLP, KRS, and PP contributed to the writing and/or critical revision of the manuscript.

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Correspondence to Peter Penzes.

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Piguel, N.H., Yoon, S., Gao, R. et al. Lithium rescues dendritic abnormalities in Ank3 deficiency models through the synergic effects of GSK3β and cyclic AMP signaling pathways. Neuropsychopharmacol. 48, 1000–1010 (2023). https://doi.org/10.1038/s41386-022-01502-2

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