Disruption of circadian rhythms by ambient light during neu-rodevelopment leads to autistic-like molecular and behavioral alterations in adult mice

Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8h/8h Light/Dark (LD) cycle was applied during E1-P42, we investigated molecular and behavioral changes after circadian disruption in mice. Adult SD mice fully entrained to the 8h/8h LD cycle and their circadian oscillations of clock protein PERI-OD1 and PERIOD2 were disrupted in the suprachiasmatic nucleus and the hippocampus. RNA-seq revealed changes in the transcriptome associated with neurodevelopment, translational control, and autism. Western blotting and immunostaining identified hyperactivation of the mTOR and MAPK signaling and enhanced global protein synthesis in the hippocampus of SD mice. Electrophysiological recording uncovered enhanced excitatory but attenuated inhibitory synaptic transmission in the hippocampal CA1 pyramidal neurons. These functional changes are corroborated by immature dendritic spine morphology in these neurons. Lastly, autistic-like be-havioral changes, including impaired social interaction and communication, increased repetitive behaviors and impaired novel object recognition and location memory, were found in SD mice. Together, these findings demonstrate autistic-like phenotypes in SD mice and highlight a critical role for circadian rhythm in neurodevelopment. Overall design: RNA-seq experiment of control mice and short day mice, 3 biological replicates for each condition;