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High-Fat Diet Exacerbates Autistic-Like Restricted Repetitive Behaviors and Social Abnormalities in CC2D1A Conditional Knockout Mice

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Abstract

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders characterized by deficits in social communication, social interaction, and the presence of restricted repetitive behaviors. The cause of ASD involves complex interactions between genetic and environmental factors. Haploinsufficiency of the Coiled-coil and C2 domain containing 1A (Cc2d1a) gene is causally linked to ASD, and obesity has been associated with worse outcomes for ASD. High-fat diet (HFD) feeding leads to the development of obesity and metabolic dysfunction; however, the effect of HFD on pre-existing autistic-like phenotypes remains to be clarified. Here, we report that male Cc2d1a conditional knockout (cKO) mice fed with HFD, from weaning onwards and throughout the experimental period, show a marked aggravation in autistic-like phenotypes, manifested in increased restricted repetitive behaviors and impaired performance in the preference for social novelty, but not in sociability and cognitive impairments assessed using the object location memory, novel object recognition, and Morris water maze tests. HFD feeding also results in increased numbers of reactive microglia and astrocytes, and exacerbates reductions in dendritic complexity and spine density of hippocampal CA1 pyramidal neurons. Furthermore, we demonstrate that chronic treatment with minocycline, a semisynthetic tetracycline-derived antibiotic, rescues the observed behavioral and morphological deficits in Cc2d1a cKO mice fed with HFD. Collectively, these findings highlight an aggravating role of HFD in pre-existing autistic-like phenotypes and suggest that minocycline treatment can alleviate abnormal neuronal morphology and behavioral symptoms associated with ASD resulted from the interplay between genetic and environmental risk factors.

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Data Availability

The authors confirm that all data generated and analyzed during this study are either included in this published article or available from the corresponding authors upon reasonable request.

Abbreviations

ANOVA :

Analysis of variance

ASD :

Autism spectrum disorder

BTBR :

BTBR T+ Itpr3tf/J

CA1 :

Cornu ammonis 1

Cc2d1a :

Coiled-coil and C2 domain containing 1A

Cc2d1a f / f :

Cc2d1a Floxed

cKO:

Conditional knockout

Env :

Environmental

Gen :

Genetic

GFAP :

Glial fibrillary acidic protein

HFD :

High-fat diet

MWM :

Morris water maze

Iba1 :

Ionized calcium-binding adapter molecule-1

ND :

Normal diet

NOR :

Novel object recognition

OLM :

Object location memory

Mino :

Minocycline

P0 :

Postnatal day 0

PBS :

Phosphate-buffered saline

PFA :

Paraformaldehyde

RM :

Repeated measured

WT :

Wild-type

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Acknowledgements

The authors thank the technical services provided by the Bio-image Core Facility of the National Core Facility Program for Biotechnology, Ministry of Science and Technology, Taiwan.

Funding

This work was supported by research grants from the National Health Research Institute (NHRI-EX109-10912NI; NHRI-EX110-10912NI) and the Ministry of Science and Technology (109–2320-B-006–039-MY3 and 110–2320-B-006–036-MY3), Taiwan.

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  1. Yu-Chiao Wang and Chin-Hao Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, National Cheng Kung University, University Rd, No. 1, Tainan, 70101, Taiwan

    Yu-Chiao Wang, Cheng-Yi Yang & Kuei-Sen Hsu

  2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan

    Chin-Hao Chen & Kuei-Sen Hsu

  3. Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan

    Pin Ling

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Contributions

YCW, CHC, CYY, and KSH designed research; YCW, CHC, and CYY performed research; YCW, CHC, and CYY analyzed data; PL provided Cc2d1af/f mice; YCW, CHC, and KSH wrote the paper.

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Correspondence to Kuei-Sen Hsu.

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Wang, YC., Chen, CH., Yang, CY. et al. High-Fat Diet Exacerbates Autistic-Like Restricted Repetitive Behaviors and Social Abnormalities in CC2D1A Conditional Knockout Mice. Mol Neurobiol 60, 1331–1352 (2023). https://doi.org/10.1007/s12035-022-03146-1

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