Behavioral Consequences of Disrupted MET Signaling

Background: Utilizing genetically modified mouse lines to dissect the role of specific genes in the neurobiological underpinnings of neurodevelopmental disorders is an important approach. Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Subsequent studies have shown a role for MET in functional and structural cortical connectivity in typically developing individuals and those with autism spectrum disorder. Furthermore, our studies have illuminated a role for Met in dendritic and spine architecture and excitatory drive in the cortex of mouse models of altered Met signaling. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of cerebral cortex neurons. These mice were then tested to determine the developmental and long-term behavioral consequences of disrupting Met signaling.  

Objectives: The objective of these studies was to test our hypothesis that disruption of Met signaling during development has functional consequences on the maturation of cortical circuits and behaviors that are altered in autism. These studies define autism relevant specific social, emotional and cognitive behaviors caused by developmental disruption of Met cortical signaling.

Methods: We generated two conditional mouse lines in which Met is deleted from select populations: 1) Met^fx/fx/Emx1^cre (deleted from all cells arising from the dorsal pallium) and 2) Met^fx/fx/Nestin^cre (deleted from all neural cells). A battery of behavioral tests was performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders, including ASD, and that, are in part sub-served by circuits that express Met. Multiple cohorts of n=6 mice per genotype were tested in early adulthood on rotarod, activity chamber, elevated plus maze, spontaneous alternation in the t-maze, olfactory dishabituation, social novelty preference, marble burying, and contextual fear conditioning.

Results: Across multiple cohorts of animals we found that the null Met^fx/+/Emx1^cre mice display significant hypoactivity in the activity chamber and in the t-maze despite normal performance on the rotarod.  Additionally, these animals show a deficit in spontaneous alternation. The null Met^fx/+/Emx1^cre mice show normal anxiety, olfactory dishabituation, social novelty preference, contextual fear conditioning, and marble burying. The null Met^fx/fx/Nestin^cre mice display deficits in contextual fear conditioning, and a weak deficit in sociability in the social novelty preference task. The null Met^fx/fx/Nestin^cre mice show normal performance on rotarod and activity chamber, anxiety, spontaneous alternation, olfactory dishabituation, and marble burying.

Conclusions: These data suggest a complex contribution of Met in the development of social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon the circuit-specific deletion pattern. The null Met^fx/fx/Nestin^cre mice (Met deleted from every cortical cell) show behavioral phenotypes consistent with autism. In contrast, the null Met^fx/+/Emx1^cre mice (Met deleted from all cells arising from the dorsal pallium) show a different behavioral phenotype, with decreased exploratory behavior and memory. Future studies will determine the impact of environmental interactions with the deletion of Met from the Met^fx/fx/Nestin^cre mice on further social, emotional, and cognitive behaviors.