Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior.

Barbara L Thompson,Pat Levitt

doi:10.1186/s11689-015-9131-8

Abstract

BackgroundOur laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. 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 central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression.MethodsMating of Emx1cre and Metfx/fx mice eliminates receptor signaling from all cells arising from the dorsal pallium. Metfx/fx and Nestincre crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met.ResultsMetfx/fx/Emx1cre null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Metfx/fx; fx/+/Nestincre null and heterozygous mice exhibited deficits in contextual fear conditioning, and Metfx/+/Nestincre heterozygous mice spent less time in the closed arms of the elevated plus maze.ConclusionsThese data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-015-9131-8) contains supplementary material, which is available to authorized users.

Highlights

Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk
We report that the behavioral phenotypes vary by line and gene dose, consistent with a complex and heterogeneous impact of reducing Met expression in specific circuits, brain circuits in the mouse
Conditional Metfx/fx/Emx1cre mutant mice were produced by mating mice homozygous for a Met allele, in which exon 16 is flanked by loxP sites originally generated in the 129SV mouse strain [33], to Emx1cre mice originally generated in the 129S2/SvPas strain [31] that were heterozygous for the floxed allele (Metfx/+/Emx1cre)

Summary

Introduction

Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. Results: Metfx/fx/Emx1cre null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Genetic studies have demonstrated that a 5′ promoter polymorphism is associated with increased risk for autism spectrum disorder (ASD) [16,17,18,19]. This risk variant is functional, reducing MET transcription in both typical and ASD subjects [20,21,22]. The risk variant is associated with distinct gray matter growth patterns in specific regions of the human brain [26]

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