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

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.