Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis
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BACKGROUND: The inbred mouse strain BTBR T+ tf/J (BTBR) exhibits behavioral deficits that mimic the core deficits of autism. Neuroanatomically, the BTBR strain is also characterized by a complete absence of the corpus callosum. The goal of this study was to identify novel molecular and cellular changes in the BTBR mouse, focusing on neuronal, synaptic, glial and plasticity markers in the limbic system as a model for identifying putative molecular and cellular substrates associated with autistic behaviors. METHODS: Forebrains of 8 to 10-week-old male BTBR and age-matched C57Bl/6J control mice were evaluated by immunohistochemistry using free-floating and paraffin embedded sections. Twenty antibodies directed against antigens specific to neurons, synapses and glia were used. Nissl, Timm and acetylcholinesterase (AchE) stains were performed to assess cytoarchitecture, mossy fibers and cholinergic fiber density, respectively. In the hippocampus, quantitative stereological estimates for the mitotic marker bromodeoxyuridine (BrdU) were performed to determine hippocampal progenitor proliferation, survival and differentiation, and brain-derived neurotrophic factor (BDNF) mRNA was quantified by in situ hybridization. Quantitative image analysis was performed for NG2, doublecortin (DCX), NeuroD, GAD67 and Poly-Sialic Acid Neural Cell Adhesion Molecule (PSA-NCAM). RESULTS: In midline structures including the region of the absent corpus callosum of BTBR mice, the myelin markers 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and myelin basic protein (MBP) were reduced, and the oligodendrocyte precursor NG2 was increased. MBP and CNPase were expressed in small ectopic white matter bundles within the cingulate cortex. Microglia and astrocytes showed no evidence of gliosis, yet orientations of glial fibers were altered in specific white-matter areas. In the hippocampus, evidence of reduced neurogenesis included significant reductions in the number of doublecortin, PSA-NCAM and NeuroD immunoreactive cells in the subgranular zone of the dentate gyrus, and a marked reduction in the number of 5-bromo-2'-deoxyuridine (BrdU) positive progenitors. Furthermore, a significant and profound reduction in BDNF mRNA was seen in the BTBR dentate gyrus. No significant differences were seen in the expression of AchE, mossy fiber synapses or immunoreactivities of microtubule-associated protein MAP2, parvalbumin and glutamate decarboxylase GAD65 or GAD67 isoforms. CONCLUSIONS: We documented modest and selective alterations in glia, neurons and synapses in BTBR forebrain, along with reduced neurogenesis in the adult hippocampus. Of all markers examined, the most distinctive changes were seen in the neurodevelopmental proteins NG2, PSA-NCAM, NeuroD and DCX. Our results are consistent with aberrant development of the nervous system in BTBR mice, and may reveal novel substrates to link callosal abnormalities and autistic behaviors. The changes that we observed in the BTBR mice suggest potential novel therapeutic strategies for intervention in autism spectrum disorders.
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Other white matter changes in BTBR mice include abnormal posterior interhemispheric connectivity and skewed orientation of glial cells in some affected white matter tracts.
“Other white matter changes in BTBR mice include abnormal posterior interhemispheric connectivity [240] and skewed orientation of glial cells in some of the affected white matter tracts [338].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [338]
BTBR mice have more serotonin-expressing neurons in the caudal portions of the median and dorsal raphe but decreased axon terminals in the hippocampal CA1, decreased adult neurogenesis in the dentate gyrus, upregulation of postnatal turnover of excitatory synapses in the anterior frontal cortex, and unaltered synaptic density and PSD thickness in the somatosensory cortex.
“The presence of more serotonin-expressing neurons in the caudal portions of the median and dorsal raphe but decreased axon terminals in the hippocampal CA1 [134], decreased adult neurogenesis in the dentate gyrus [338], upregulation of postnatal turnover of excitatory synapses in the anterior frontal cortex [172], and unaltered synaptic density and PSD thickness in the somatosensory cortex [381]”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [338]
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Flagged first, then by citations
Research works printed but not linked: 1
- O'Neill SP Characterization of myelin and glial markers in the brain of the BTBR T+ tf/J mouse, a model of autistic-like social behavior and callosal agenesis Keystone Conference "Towards an understanding of the pathophysiology of autism 201021339216
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- Authors
- Stephenson, D. T., O'Neill, S. M., Narayan, S., Tiwari, A., Arnold, E., Samaroo, H. D., Du, F., Ring, R. H., Campbell, B., Pletcher, M., Vaidya, V. A., & Morton, D.
- Affiliations
- Pfizer (United States) (US)
- Tata Institute of Fundamental Research (IN)
- Corresponding author
- Stephenson, Diane T
- ORCID
- Venue
- Molecular Autism
- Published
- 2011
- Volume
- 2
- Issue
- 1
- Pages
- 7
- ISSN
- 2040-2392 (ISSN-L)
- PMC
- PMC3135520
- OpenAlex
- W2029887906
- Cited by
- 180
- References
- 118
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 16 · 2023: 9 · 2022: 14 · 2021: 19 · 2020: 10 · 2019: 15 · 2018: 5 · 2017: 19 · 2016: 13 · 2015: 12 · 2014: 7 · 2013: 11 · 2012: 7
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Autism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Pfizer
- University of California, San Francisco
- National Institute of Mental Health
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- autism spectrum disorder, agenesis of the corpus callosum, hippocampal neurogenesis, adult neurogenesis, brain-derived neurotrophic factor, doublecortin, PSA-NCAM, neurogenic differentiation, oligodendrocyte precursor cells, myelin basic protein, CNPase, mossy fibers, cholinergic fibers, dentate gyrus, limbic system, white matter
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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