DISC1 in Astrocytes Influences Adult Neurogenesis and Hippocampus-Dependent Behaviors in Mice

Neuropsychopharmacology. 2017 Oct;42(11):2242-2251. doi: 10.1038/npp.2017.129. Epub 2017 Jun 20.

Abstract

The functional role of genetic variants in glia in the pathogenesis of psychiatric disorders remains poorly studied. Disrupted-In-Schizophrenia 1 (DISC1), a genetic risk factor implicated in major mental disorders, has been implicated in regulation of astrocyte functions. As both astrocytes and DISC1 influence adult neurogenesis in the dentate gyrus (DG) of the hippocampus, we hypothesized that selective expression of dominant-negative C-terminus-truncated human DISC1 (mutant DISC1) in astrocytes would affect adult hippocampal neurogenesis and hippocampus-dependent behaviors. A series of behavioral tests were performed in mice with or without expression of mutant DISC1 in astrocytes during late postnatal development. In conjunction with behavioral tests, we evaluated adult neurogenesis, including neural progenitor proliferation and dendrite development of newborn neurons in the DG. The ameliorative effects of D-serine on mutant DISC1-associated behaviors and abnormal adult neurogenesis were also examined. Expression of mutant DISC1 in astrocytes decreased neural progenitor proliferation and dendrite growth of newborn neurons, and produced elevated anxiety, attenuated social behaviors, and impaired hippocampus-dependent learning and memory. Chronic treatment with D-serine ameliorated the behavioral alterations and rescued abnormal adult neurogenesis in mutant DISC1 mice. Our findings suggest that psychiatric genetic risk factors expressed in astrocytes could affect adult hippocampal neurogenesis and contribute to aspects of psychiatric disease through abnormal production of D-serine.

MeSH terms

  • Animals
  • Animals, Newborn
  • Anxiety / drug therapy
  • Anxiety / genetics
  • Anxiety / pathology
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Disease Models, Animal
  • Doxycycline / pharmacology
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / cytology*
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurogenesis / genetics*
  • Neurons / drug effects
  • Neurons / metabolism
  • Recognition, Psychology / drug effects
  • Serine / pharmacology

Substances

  • Disc1 protein, mouse
  • Glial Fibrillary Acidic Protein
  • Nerve Tissue Proteins
  • Serine
  • Doxycycline