Adult neurogenesis in the ventral hippocampus decreased among animal models of neurodevelopmental disorders

Front Neural Circuits. 2024 Dec 23:18:1504191. doi: 10.3389/fncir.2024.1504191. eCollection 2024.

Abstract

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and communication, along with restricted and repetitive behaviors. Both genetic and environmental factors contribute to ASD, with prenatal exposure to valproic acid (VPA) and nicotine being linked to increased risk. Impaired adult hippocampal neurogenesis, particularly in the ventral region, is thought to play a role in the social deficits observed in ASD.

Methods: In this study, we investigated social behavior and adult hippocampal neurogenesis in C57BL/6J mice prenatally exposed to VPA or nicotine, as well as in genetically modified ASD models, including IQSEC2 knockout (KO) and NLGN3-R451C knock-in (KI) mice. Sociability and social novelty preference were evaluated using a three-chamber social interaction test. Adult hippocampal neurogenesis was assessed by BrdU and DCX immunofluorescence to identify newborn and immature neurons.

Results: VPA-exposed mice displayed significant deficits in social interaction, while nicotine-exposed mice exhibited mild impairment in social novelty preference. Both IQSEC2 KO and NLGN3-R451C KI mice demonstrated reduced adult neurogenesis, particularly in the ventral hippocampus, a region associated with social behavior and emotion. Across all ASD mouse models, a significant reduction in BrdU+/NeuN+ cells in the ventral hippocampus was observed, while dorsal hippocampal neurogenesis remained relatively unaffected. Similar reductions in DCX-positive cells were identified in VPA, nicotine, and NLGN3-R451C KI mice, indicating impaired proliferation or differentiation of neuronal progenitors.

Discussion: These findings suggest that impaired adult neurogenesis in the ventral hippocampus is a common hallmark across ASD mouse models and may underlie social behavior deficits. This study provides insight into region-specific neurogenic alterations linked to ASD pathophysiology and highlights potential targets for therapeutic interventions.

Keywords: IQSEC2; adult hippocampal neurogenesis; autism spectrum disorder; neuroligin 3; prenatal nicotine exposure; valproic acid.

MeSH terms

  • Animals
  • Autism Spectrum Disorder / chemically induced
  • Autism Spectrum Disorder / physiopathology
  • Disease Models, Animal*
  • Doublecortin Protein
  • Female
  • Hippocampus* / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Mice, Knockout
  • Neurodevelopmental Disorders / chemically induced
  • Neurodevelopmental Disorders / pathology
  • Neurodevelopmental Disorders / physiopathology
  • Neurogenesis* / drug effects
  • Neurogenesis* / physiology
  • Nicotine / pharmacology
  • Pregnancy
  • Prenatal Exposure Delayed Effects / physiopathology
  • Social Behavior*
  • Social Interaction / drug effects
  • Valproic Acid* / pharmacology

Substances

  • Valproic Acid
  • Doublecortin Protein
  • Nicotine
  • Dcx protein, mouse

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants KAKENHI 21K07293 (TM) and 23H02575 (KT); the Grant-in-Aid for Transformative Research Areas (A) 21H05685 (TM) and 23H04227 (KT); JST SPRING, grant number JPMJSP2144 (Shinshu University to LS); the Smoke Research Foundation (TM); the Takeda Science Foundation (TM and KT); the Naito Foundation (TM); the IQSEC2 Research and Advocacy Foundation Research Grant Program (#2024-02 to TM); and SENSHIN Medical Research Foundation (KT).