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Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories.
- Source :
-
Cerebral cortex (New York, N.Y. : 1991) [Cereb Cortex] 2018 Jul 01; Vol. 28 (7), pp. 2495-2506. - Publication Year :
- 2018
-
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.
- Subjects :
- Age Factors
Animals
Animals, Newborn
Brain diagnostic imaging
Brain metabolism
Brain ultrastructure
Brain Mapping
Connectome
Disease Models, Animal
Fragile X Mental Retardation Protein metabolism
Image Processing, Computer-Assisted
Luminescent Proteins genetics
Luminescent Proteins metabolism
Magnetic Resonance Imaging
Membrane Proteins metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins metabolism
Neural Pathways diagnostic imaging
Oxygen blood
Transduction, Genetic
Red Fluorescent Protein
Autistic Disorder complications
Autistic Disorder genetics
Autistic Disorder pathology
Brain growth & development
Fragile X Mental Retardation Protein genetics
Membrane Proteins genetics
Nerve Tissue Proteins genetics
Neural Pathways growth & development
Neural Pathways pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2199
- Volume :
- 28
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cerebral cortex (New York, N.Y. : 1991)
- Publication Type :
- Academic Journal
- Accession number :
- 29901787
- Full Text :
- https://doi.org/10.1093/cercor/bhy046