Aberrant Sensory Processing in Mice Lacking Autism Associated Met Receptor Function: A Role for Insulin?

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 cerebral cortex at rostral levels in transgenic mice expressing a kinase-dead Met in the Emx1 lineage. Earlier studies imply defects in cortical connectivity after loss of Met signaling in the Met-Emx1 mice. Behavioral observations indicate potential altered sensory processing in Met-Emx1 mice.

Objectives:  We investigated sensory processing in mice lacking functional Met receptor in the cerebral cortex (Met-Emx1).  The study focused on the rodent whisker system and the inhibitory response in the barrel cortex to reveal underlying cellular mechanisms of decreased or absent Met signaling. 

Methods:  We used in vitro recordings from thalamocortical slices to test our hypotheses that loss of Met altered the balance of excitation to inhibition (AMPA/GABA ratio).  We also measured the multiple input index and paired pulse ratios of EPSCs and IPSCs. Immunohistochemistry and immunoblots were used to confirm expression levels and anatomical alterations.

Results:  Our data show altered excitation/inhibition (E/I) balance at the thalamocortical synapse. In addition, treatment with insulin, which recruits GABA-A receptors to restore inhibition in control slices, failed to change the E/I balance in slices lacking a single copy of functional Met.  

Conclusions:  Our results suggest that the sensory circuitry in the Met-Emx1 cortex exhibits impaired E/I balance and is resistant to insulin.  These data suggest the approved therapies for diabetes may be helpful in the prevention or amelioration of the symptoms associated with ASD, especially in the individuals who have the common autism associated MET alleles.