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

Researchers studied mice with autism-like traits and found that a high-fat diet made their repetitive behaviors and social difficulties worse. The high-fat diet also caused brain inflammation and changes to brain cells. However, treating the mice with an antibiotic called minocycline helped improve both their behavior and brain health. This suggests that diet might affect autism symptoms in those who are already genetically at risk.

This study examined how high-fat diet (HFD) affects autistic behaviors in genetically predisposed mice with CC2D1A gene mutations. Male mice fed HFD from weaning showed worsened autism-like behaviors, including increased repetitive behaviors and reduced preference for social novelty, though sociability and cognitive function remained unchanged. HFD also increased brain inflammation (reactive microglia and astrocytes) and reduced neural complexity in the hippocampus. Treatment with minocycline, an antibiotic with anti-inflammatory properties, reversed these behavioral and brain changes.

The findings suggest that dietary factors may worsen autism symptoms in genetically vulnerable individuals through neuroinflammatory mechanisms.

Results suggest high-fat diets may worsen autism symptoms through inflammatory mechanisms, particularly in genetically vulnerable individuals. Anti-inflammatory interventions like minocycline may offer therapeutic potential. Dietary counseling focusing on reducing high-fat foods could be beneficial for autism management.

Animal study using genetically modified mice may not translate directly to humans. Sample size not reported. Limited to male mice only. Short-term intervention study without long-term follow-up data.

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.