DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling

Mol Psychiatry. 2018 Feb;23(2):467-475. doi: 10.1038/mp.2016.184. Epub 2016 Oct 18.

Abstract

Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/β-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls. Many of these SNVs alter Wnt/β-catenin signaling activity of the neurally predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/β-catenin pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety
  • Anxiety Disorders
  • Dendritic Spines / genetics*
  • Dendritic Spines / metabolism
  • Depression
  • Depressive Disorder
  • Glutamate Plasma Membrane Transport Proteins / metabolism
  • Glycogen Synthase Kinase 3 / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Mental Disorders / genetics
  • Mice
  • Mice, Knockout
  • Polymorphism, Single Nucleotide / genetics
  • Pyramidal Cells / physiology
  • Social Behavior
  • Synapses / metabolism
  • Wnt Signaling Pathway / physiology
  • beta Catenin / metabolism

Substances

  • Dixdc1 protein, mouse
  • Glutamate Plasma Membrane Transport Proteins
  • Intracellular Signaling Peptides and Proteins
  • beta Catenin
  • Glycogen Synthase Kinase 3