Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity
Open accessAbstract
Autism is a heritable disorder, with over 250 associated genes identified to date, yet no single gene accounts for >1-2% of cases. The clinical presentation, behavioural symptoms, imaging and histopathology findings are strikingly heterogeneous. A more complete understanding of autism can be obtained by examining multiple genetic or behavioural mouse models of autism using magnetic resonance imaging (MRI)-based neuroanatomical phenotyping. Twenty-six different mouse models were examined and the consistently found abnormal brain regions across models were parieto-temporal lobe, cerebellar cortex, frontal lobe, hypothalamus and striatum. These models separated into three distinct clusters, two of which can be linked to the under and over-connectivity found in autism. These clusters also identified previously unknown connections between Nrxn1α, En2 and Fmr1; Nlgn3, BTBR and Slc6A4; and also between X monosomy and Mecp2. With no single treatment for autism found, clustering autism using neuroanatomy and identifying these strong connections may prove to be a crucial step in predicting treatment response.
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16p11.2 hemideletion mice have larger volumes in the hypothalamus, midbrain, cerebellar cortex, striatum, nucleus accumbens, and globus pallidus.
“Increased volumes of several brain areas, including the hypothalamus, midbrain, cerebellar cortex, striatum, nucleus accumbens and globus pallidus, are observed in 16p11.2+/− mice (Mills, Dolmetsch) [4, 5, 96]”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [96]
This work supports the growing notion that genetic etiologies may affect different phenotypes and brain circuits.
“This work supports the growing notion that genetic etiologies may affect different phenotypes and brain circuits (Ellegood et al. 2015; Connor et al. 2016; Huang et al. 2016; Wang et al. 2016).”
From Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories (2018) · cites this paper as Ellegood et al. 2015
Similar to the most consistent finding in humans, an increase in the frontal and parieto-temporal lobes and decreased volume of the cerebellar cortex were observed in one of three subgroups (group 1) identified among 26 investigated ASD mouse models.
“Similar to the most consistent finding in humans [94, 95], an increase in the frontal and parieto-temporal lobes and decreased volume of the cerebellar cortex were observed in one of the three subgroups (“group 1”) identified among the 26 investigated models [75].”
Knockout mice in group 1 including null mutants for En2, Fmr1 and Shank3 show an increase in the frontal and parieto-temporal lobes and a volume decrease in the cerebellum, as well as a decrease in PV staining.
“Knockout mice in group 1 including null mutants for En2, Fmr1 and Shank3 show an increase in the frontal and parieto-temporal lobes and a volume decrease in the cerebellum, as well as a decrease in PV staining.”
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References 52 · Cited by 288
- Authors
- Ellegood, J., Anagnostou, E., Babineau, B. A., Crawley, J. N., Lin, L., Genestine, M., DiCicco-Bloom, E., Lai, J. K. Y., Foster, J. A., Peñagarikano, O., Geschwind, D. H., Pacey, L. K., Hampson, D. R., Laliberté, C. L., Mills, A. A., Tam, E., Osborne, L. R., Kouser, M., Espinosa-Becerra, F., Xuan, Z., Powell, C. M., Raznahan, A., Robins, D. M., Nakai, N., Nakatani, J., Takumi, T., van Eede, M. C., Kerr, T. M., Muller, C., Blakely, R. D., Veenstra-VanderWeele, J., Henkelman, R. M., & Lerch, J. P.
- Affiliations
- Hospital for Sick Children (CA)
- Holland Bloorview Kids Rehabilitation Hospital (CA)
- National Institutes of Health (US)
- McMaster University (CA)
- University of California, Los Angeles (US)
- University of Toronto (CA)
- Cold Spring Harbor Laboratory (US)
- The University of Texas Southwestern Medical Center (US)
- University of Michigan (US)
- RIKEN Center for Brain Science (JP)
- Vanderbilt University (US)
- Corresponding author
- Ellegood, J
- Lerch, J P
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2014-09-09
- Volume
- 20
- Issue
- 1
- Pages
- 118-125
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4426202
- OpenAlex
- W2016423032
- Cited by
- 288
- References
- 52
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 24 · 2023: 23 · 2022: 18 · 2021: 33 · 2020: 26 · 2019: 29 · 2018: 27 · 2017: 34 · 2016: 28 · 2015: 18 · 2014: 1
- FWCI
- 15.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (25242077)
- National Institute of Mental Health (P50MH096972, R01MH094604, R01MH081164, R01MH093697)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD069560, R21HD065290)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- autism spectrum disorder, mouse models of autism, autism heterogeneity, brain connectivity, EN2, FMR1 gene, neuroligin-3, serotonin transporter, monosomy X, MeCP2, treatment response prediction
- MeSH terms
- Animals, Autistic Disorder, Brain, Disease Models, Animal, Multigene Family, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Mice, Inbred BALB C, Mice, Transgenic, Mice
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