Heterozygous Cc2d1a mice show sex-dependent changes in the Beclin-1/p62 ratio with impaired prefrontal cortex and hippocampal autophagy.

Scientists studied mice with changes in a gene (Cc2d1a) linked to autism risk. They found problems with how brain cells clean themselves (autophagy) in memory and thinking areas of the brain. These problems were different between male and female mice. Surprisingly, even normal offspring of affected parent mice showed some changes, suggesting these effects might be passed down. This research helps us understand how autism might develop at the cellular level.

This preclinical study examined autophagy (cellular cleanup) mechanisms in mice with mutations in the Cc2d1a gene, which is associated with autism risk in humans. Researchers analyzed autophagy markers in brain regions including hippocampus, prefrontal cortex, hypothalamus, and cerebellum. Key findings included decreased autophagy and altered protein ratios in the hippocampus, with sex-dependent differences in gene and protein expression. Notably, autophagy changes in heterozygous parent mice were transmitted to wild-type offspring, suggesting potential inheritance patterns.

The study proposes that disrupted autophagy may contribute to synaptic alterations characteristic of autism spectrum disorders, providing insights into potential biological mechanisms underlying ASD.

Findings suggest autophagy dysfunction may represent a novel therapeutic target for autism interventions. Sex-specific differences warrant consideration in treatment approaches. Potential inheritance patterns may inform genetic counseling discussions with families.

Study conducted in animal model only, limiting direct translation to humans. Sample size not reported. Specific mechanisms linking autophagy dysfunction to autism behaviors not established. Long-term developmental outcomes not assessed.

Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders characterized by repetitive behaviors, lack of social interaction and communication. CC2D1A is identified in patients as an autism risk gene. Recently, we suggested that heterozygous Cc2d1a mice exhibit impaired autophagy in the hippocampus. We now report the analysis of autophagy markers (Lc3, Beclin and p62) in different regions hippocampus, prefrontal cortex, hypothalamus and cerebellum, with an overall decrease in autophagy and changes in Beclin-1/p62 ratio in the hippocampus.

We observed sex-dependent variations in transcripts and protein expression levels. Moreover, our analyses suggest that alterations in autophagy initiated in Cc2d1a heterozygous parents are variably transmitted to offspring, even when the offspring's genotype is wild type. Aberration in the autophagy mechanism may indirectly contribute to induce synapse alteration in the ASD brain.