Transplantation of mesenchymal stem cells reverses behavioural deficits and impaired neurogenesis caused by prenatal exposure to valproic acid

Oncotarget. 2017 Mar 14;8(11):17443-17452. doi: 10.18632/oncotarget.15245.

Abstract

Neurodevelopmental impairment can affect lifelong brain functions such as cognitive and social behaviour, and may contribute to aging-related changes of these functions. In the present study, we hypothesized that bone marrow-derived mesenchymal stem cells (MSC) administration may repair neurodevelopmental behavioural deficits by modulating adult hippocampal neurogenesis. Indeed, postnatal intracerebral transplantation of MSC has restored cognitive and social behaviour in mice prenatally exposed to valproic acid (VPA). MSC transplantation also restored post-developmental hippocampal neurogenesis, which was impaired in VPA-exposed mice displaying delayed differentiation and maturation of newly formed neurons in the granular cell layer of the dentate gyrus. Importantly, a statistically significant correlation was found between neuronal differentiation scores and behavioural scores, suggesting a mechanistic relation between the two. We thus conclude that post-developmental MSC administration can overcome prenatal neurodevelopmental deficits and restore cognitive and social behaviours via modulation of hippocampal adult neurogenesis.

Keywords: Gerotarget; behavioural disorders; doublecortin (DCX); hippocampal neurogenesis; mesenchymal stem cells (MSC); valproic acid (VPA).

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Disease Models, Animal
  • Female
  • GABA Agents / toxicity
  • Hippocampus*
  • Immunohistochemistry
  • Maze Learning
  • Mesenchymal Stem Cell Transplantation / methods*
  • Mice
  • Neurodevelopmental Disorders / chemically induced
  • Neurodevelopmental Disorders / complications*
  • Neurogenesis* / physiology
  • Neurons / cytology
  • Pregnancy
  • Prenatal Exposure Delayed Effects / etiology
  • Prenatal Exposure Delayed Effects / therapy*
  • Social Behavior
  • Valproic Acid / toxicity

Substances

  • GABA Agents
  • Valproic Acid