Wnt/β-Catenin Pathway Contributions to Dendritic Spine and Glutamatergic Synapse Formation Responsive to Lithium-Mediated GSK3 Inhibition

Stanley, Robert, Martin, Pierre-Marie, Ross, Adam, Freitas, Andiara, Iafrati, Jillian, Moyer, Caitlin, Brumback, Audrey, Pirooznia, Mehdi, McCombie, W. Richard, Potash, James, Zandi, Peter, Purcell, Shaun, Sanders, Stephan, Zuo, Yi, Sohal, Vikaas, Cheyette, Benjamin (2017) Wnt/β-Catenin Pathway Contributions to Dendritic Spine and Glutamatergic Synapse Formation Responsive to Lithium-Mediated GSK3 Inhibition. Biological Psychiatry, 81 (10, Su). S286. ISSN 0006-3223

URL: http://www.sciencedirect.com/science/article/pii/S...
DOI: 10.1016/j.biopsych.2017.02.773

Abstract

Background A major direct target of lithium is the metalloenzyme GSK3, the central kinase in the Wnt/β-catenin pathway broadly involved in neural development. Methods We have investigated neurodevelopmental and behavioral functions of DIXDC1, which regulates Wnt/β-catenin signaling including late in neural development and postnatally. We have studied a Dixdc1 knock-out (KO) mouse line, applying in vitro and in vivo experimental approaches to assess neurodevelopment, neural activity, dendritic spine dynamics, animal behavior, and responsiveness to lithium and a selective GSK3 inhibitor. This has been accompanied by sequencing of the human DIXDC1 locus in several psychiatric disorders including bipolar disorder, and rescue and gain-of-function experiments involving rare human missense single nucleotide variants (SNVs) that alter the protein׳s signaling activity. Results In mice, loss of Dixdc1 leads to dose-sensitive deficits in behavioral assays including models of depression; this is responsive to lithium as well as to a selective GSK3-inhibitor. Forebrain cortical pyramidal neurons from Dixdc1KO mice have reduced dendritic spine and glutamatergic synapse density correctable by lithium or a selective GSK3 inhibitor. Many of the rare SNVs found more frequently in psychiatric patients affect Wnt/β-catenin activity of the encoded protein. They also alter the above neurodevelopmental parameters when expressed in differentiating pyramidal neurons. Conclusions Our data support a role for DIXDC1 in formation and/or stability of dendritic spines and synapses in forebrain pyramidal neurons upstream of complex behaviors including depression. Our data further suggest that this occurs through the protein’s activity in the Wnt/β-catenin signaling pathway within neurons, and that this responds to GSK3 inhibition by lithium.

Item Type: Paper
Additional Information: Meeting Abstract
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > catenins
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > dendritic cells > dendritic spines
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > dendritic cells > dendritic spines
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > dendritic cells > dendritic spines

organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions > synapse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Wnt
CSHL Authors:
Communities: CSHL labs > McCombie lab
Depositing User: Matt Covey
Date Deposited: 05 Jun 2017 20:10
Last Modified: 05 Jun 2017 20:10
URI: http://repository.cshl.edu/id/eprint/34810

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