Neuronal Abnormalities in an Autism-associated Canine Model Carrying Shank3 Mutations

Researchers from Professor ZHANG Yongqing’s team at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, have established for the first time a brain slice electrophysiology system in an autism-associated canine model and uncovered neuronal structural and functional abnormalities in Shank3 mutant dogs.

SHANK3 mutations are highly correlated with autism spectrum disorders (ASD). In rodents, the absence of Shank3 results in abnormal behaviors associated with ASD, including social interaction deficits and repetitive stereotyped behaviors. The synaptic dysfunction and dendritic spine reduction in specific brain regions due to Shank3 deficiency are considered as the neural basis leading to behavioral impairments. Given the significant differences in brain structure and social behaviors between rodents and humans, such as human interactions involving complex social cognition and understanding while rodents primarily rely on olfaction for communication, there is a challenge when translating findings from rodent models to human patients.

Dogs, co-evolving with humans over a long history and possessing complex interspecies emotional and social processing capabilities, serve as an effective animal model for studying human social behaviors and mental disorders. Thus, detecting changes in neuron activity and synaptic function in Shank3 mutant dogs is crucial for understanding the causal relationship between Shank3 mutations and abnormal social behaviors.

The researchers utilized Shank3 mutant dogs as model animals to investigate the electrophysiological function and morphological features of neurons in the prefrontal cortex, a brain region highly involved in social cognitive behaviors. The results revealed that, compared to wild-type dogs, the pyramidal neurons in the prefrontal cortex of mutant dogs exhibited increased excitability and reduced excitatory synaptic transmission. Furthermore, a reduced dendritic complexity, a lower dendritic spine density, and smaller postsynaptic density structures were also found in Shank3 mutant dogs. These phenotypes suggest that heterozygous Shank3 mutations are sufficient to induce morphological and functional abnormalities in cortical pyramidal neurons, potentially contributing to abnormal social behaviors in mutant dogs. Furthermore, this study demonstrated the feasibility of using canine brain slices to explore neural circuits and mechanisms of ASD.

This study entitled " Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs" was published in Molecular Autism on Jan 31 (https://doi.org/10.1186/s13229-024-00587-4).

 

 

 

Contact:

Professor ZHANG Yongqing

Institute of Genetics and Developmental Biology, Chinese Academy of Sciences

Email: yqzhang@genetics.ac.cn