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

Translational psychiatry (2019-10-05)
Chi Ho Chong, Qi Li, Priscilla Hoi Shan Mak, Cypress Chun Pong Ng, Eva Hin Wa Leung, Vicky Huiqi Tan, Anthony Kin Wang Chan, Grainne McAlonan, Siu Yuen Chan
RESUMEN

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.

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Sigma-Aldrich
Anti-β-Tubulin antibody, Mouse monoclonal, ~2.0 mg/mL, clone AA2, purified from hybridoma cell culture
Sigma-Aldrich
CDPPB, ≥98% (HPLC)