Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories

Cereb Cortex. 2018 Jul 1;28(7):2495-2506. doi: 10.1093/cercor/bhy046.

Abstract

Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1-/y) and contactin-associated (CNTNAP2-/-) knockout mice. Young Fmr1-/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2-/- mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Autistic Disorder* / complications
  • Autistic Disorder* / genetics
  • Autistic Disorder* / pathology
  • Brain / diagnostic imaging
  • Brain / growth & development*
  • Brain / metabolism
  • Brain / ultrastructure
  • Brain Mapping
  • Connectome
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Mental Retardation Protein / metabolism
  • Image Processing, Computer-Assisted
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Magnetic Resonance Imaging
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neural Pathways / diagnostic imaging
  • Neural Pathways / growth & development*
  • Neural Pathways / pathology*
  • Oxygen / blood
  • Transduction, Genetic

Substances

  • CNTNAP2 protein, mouse
  • Fmr1 protein, mouse
  • Luminescent Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • red fluorescent protein
  • Fragile X Mental Retardation Protein
  • Oxygen