Lrrc7 mutant mice model developmental emotional dysregulation that can be alleviated by mGluR5 allosteric modulation

Transl Psychiatry. 2019 Oct 3;9(1):244. doi: 10.1038/s41398-019-0580-9.

Abstract

LRRC7 has been identified as a candidate gene for severe childhood emotional dysregulation. Direct experimental evidence for a role of LRRC7 in the disease is needed, as is a better understanding of its impact on neuronal structure and signaling, and hence potential treatment targets. Here, we generated and analyzed an Lrrc7 mutant mouse line. Consistent with a critical role of LRRC7 in emotional regulation, mutant mice had inappropriate juvenile aggressive behavior and significant anxiety-like behavior and social dysfunction in adulthood. The pivotal role of mGluR5 signaling was demonstrated by rescue of behavioral defects with augmentation of mGluR5 receptor activity by 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB). Intra-peritoneal injection of CDPPB alleviated abnormal juvenile behavior, as well as anxiety-like behavior and hypersociability at adulthood. Furthermore, mutant primary neurons had impaired neurite outgrowth which was rescued by CDPPB treatment. In conclusion, Lrrc7 mutant mice provide a valuable tool to model childhood emotional dysregulation and persistent mental health comorbidities. Moreover, our data highlight an important role of LRRC7 in mGluR5 signaling, which is a potential new treatment target for anxiety and social dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Benzamides / pharmacology*
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Mutation
  • Neurons / physiology*
  • Pyrazoles / pharmacology*
  • Receptor, Metabotropic Glutamate 5 / physiology*
  • Sialoglycoproteins / genetics*
  • Signal Transduction

Substances

  • 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
  • Benzamides
  • Grm5 protein, mouse
  • Lrrc7 protein, mouse
  • Pyrazoles
  • Receptor, Metabotropic Glutamate 5
  • Sialoglycoproteins