Dataset Information

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder.

ABSTRACT: Myelin abnormalities have been observed in autism spectrum disorder (ASD). In this study, we seek to discover myelin-related changes in the striatum, a key brain region responsible for core ASD features, using the 16p11.2 deletion (16p11.2^±) mouse model of ASD. We found downregulated expression of multiple myelin genes and decreased myelin thickness in the striatum of 16p11.2^± mice versus wild type controls. Moreover, given that myelin is the main reservoir of brain lipids and that increasing evidence has linked dysregulation of lipid metabolism to ASD, we performed lipidomic analysis and discovered decreased levels of certain species of sphingomyelin, hexosyl ceramide and their common precursor, ceramide, in 16p11.2^± striatum, all of which are major myelin components. We further identified lack of ceramide synthase 2 as the possible reason behind the decrease in these lipid species. Taken together, our data suggest a role for myelin and myelin lipids in ASD development.

SUBMITTER: Ju J

PROVIDER: S-EPMC8416256 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder.

Ju Jun J Yang Xiuyan X Jiang Jian J Wang Dilong D Zhang Yumeng Y Zhao Xiaofeng X Fang Xiaoyi X Liao Huanquan H Zheng Lei L Li Shupeng S Hou Sheng-Tao ST Liang Liyang L Pan Yihang Y Li Huiliang H Li Ningning N

Frontiers in cellular neuroscience 20210812

Myelin abnormalities have been observed in autism spectrum disorder (ASD). In this study, we seek to discover myelin-related changes in the striatum, a key brain region responsible for core ASD features, using the 16p11.2 deletion (16p11.2<sup>±</sup>) mouse model of ASD. We found downregulated expression of multiple myelin genes and decreased myelin thickness in the striatum of 16p11.2<sup>±</sup> mice versus wild type controls. Moreover, given that myelin is the main reservoir of brain lipids ...[more]

PMID: 34483844

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Project description:Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.

Project description:BackgroundAutism spectrum disorder (ASD) is the second-most common neurodevelopmental disorder in childhood. This complex developmental disorder manifests with restricted interests, repetitive behaviors, and difficulties in communication and social awareness. The inherited and acquired causes of ASD impact many and diverse brain regions, challenging efforts to identify a shared neuroanatomical substrate for this range of symptoms. The striatum and its connections are among the most implicated sites of abnormal structure and/or function in ASD. Striatal projection neurons develop in segregated tissue compartments, the matrix and striosome, that are histochemically, pharmacologically, and functionally distinct. Immunohistochemical assessment of ASD and animal models of autism described abnormal matrix:striosome volume ratios, with an possible shift from striosome to matrix volume. Shifting the matrix:striosome ratio could result from expansion in matrix, reduction in striosome, spatial redistribution of the compartments, or a combination of these changes. Each type of ratio-shifting abnormality may predispose to ASD but yield different combinations of ASD features.MethodsWe developed a cohort of 426 children and adults (213 matched ASD-control pairs) and performed connectivity-based parcellation (diffusion tractography) of the striatum. This identified voxels with matrix-like and striosome-like patterns of structural connectivity.ResultsMatrix-like volume was increased in ASD, with no evident change in the volume or organization of the striosome-like compartment. The inter-compartment volume difference (matrix minus striosome) within each individual was 31% larger in ASD. Matrix-like volume was increased in both caudate and putamen, and in somatotopic zones throughout the rostral-caudal extent of the striatum. Subjects with moderate elevations in ADOS (Autism Diagnostic Observation Schedule) scores had increased matrix-like volume, but those with highly elevated ADOS scores had 3.7-fold larger increases in matrix-like volume.ConclusionsMatrix and striosome are embedded in distinct structural and functional networks, suggesting that compartment-selective injury or maldevelopment may mediate specific and distinct clinical features. Previously, assessing the striatal compartments in humans required post mortem tissue. Striatal parcellation provides a means to assess neuropsychiatric diseases for compartment-specific abnormalities. While this ASD cohort had increased matrix-like volume, other mechanisms that shift the matrix:striosome ratio may also increase the chance of developing the diverse social, sensory, and motor phenotypes of ASD.

Dataset Information

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder.

Publications

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder.

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