Impaired Decision Making in Mice Lacking Met Receptor in the Cerebral Cortex

Background:  MET, the gene encoding the tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF), has been identified as a common susceptibility allele for autism spectrum disorders (ASD). Both Met and HGF are expressed in the cerebral cortex during development, and HGF-Met signaling has been implicated in a number of cellular processes, including proliferation, migration, survival, and process formation. Alterations in HGF-Met signaling may therefore affect cortical development, potentially leading to neuroanatomical changes such as those thought to play a role in neurodevelopmental disorders such as ASD. We have previously found an expansion of the cortex at rostral levels in transgenic mice expressing a kinase-dead Met in the Emx1 lineage.

Objectives:  Our anatomical studies reported an abnormal expansion in frontal cortical areas in adult mice lacking Met in the cerebral cortex. We have previously demonstrated that the prefrontal cortical regions are crucial for decision making, including reversal learning and set-shifting, two behaviors in the core behavioral domains of cognitive rigidity.  We tested whether decreased Met expression impaired cognition.

Methods:  We performed a battery of behavioral tests to assess motor, sensory, emotional, social and cognitive behaviors in Met-Emx and wildtype male and female adult mice. 

Results: The Met-Emx mice demonstrated normal gross motor function and anxiety levels similar to the wildtype littermates.  However, mutant Met mice were impaired in the three chamber social interaction test.  Loss of Met allele(s) significantly affected completion of the rule learning and cognitive flexibility on the reversal and set-shifting tasks. 

Conclusions:  Mice lacking Met signaling, similar to the loss of Met function found in individuals with the MET susceptibility alleles for ASD, demonstrate parallel behavioral profiles.  The Met-Emx mice showed deficits in two core domains of ASD, social interaction and restrictive behaviors/cognitive rigidity.