Objective To observe the changes in scaffolding protein Homer protein homolog 1b and 1c（Homer1b/c），inositol 1，4，5-trisphosphate receptor（IP3R），metabotropic glutamate receptor 5（mGluR5），sh3 and multiple ankyrin repeat domains 3（Shank3） protein-related complexes，and common amino acids in the prefrontal cortex of CTNND2^-/- mice with autism，and to investigate the key targets that may be involved in the development of the disease in mice with autism. Methods Western blot（WB） was used to measure the changes in the protein expression levels of Homer1b/c，postsynaptic density-95（PSD-95），synaptophysin（SYP），and vesicular glutamate transporter 1（vGluT1） in the prefrontal cortex of CTNND2^-/- mice with autism；immunofluorescent（IF） staining was used to investigate the expression and colocalization of Homer1b/c with IP3R，mGluR5，or Shank3 proteins；co-immunoprecipitation（CO-IP） was used to observe the binding of Homer1b/c to IP3R，mGluR5 or Shank3；liquid chromatography（LC） was used to analyze the changes in common amino acids in the prefrontal cortex of mice. Results Compared with the control group，the CTNND2^-/- model mice had significant reductions in the expression of Homer1b/c（P=0.003），PSD-95（P=0.003），and SYP（P=0.046） in the prefrontal cortex and a significant reduction in the binding of Homer1b/c to IP3R，mGluR5，and Shank3 proteins，and there were no significant changes in the expression levels of the common excitatory neurotransmitter glutamate and the inhibitory neurotransmitter γ-aminobutyric acid in the prefrontal cortex（P=0.366 and 0.355），while there were significant increases in the expression levels of histidine（P=0.036） and tyrosine（P=0.030）. Conclusion There is low expression of Homer1b/c protein in the CTNND2^-/- mouse model of autism，and there is a reduction in the formation of Homer1b/c complexes with IP3R，Shank3，and mGluR5 proteins. It is speculated that low-expression Homer1b/c may be a key target for abnormal synaptic development in autism.